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Exploring Creative Drug Combinations as a Path to Better Patient Outcomes

2022; Wolters Kluwer; Volume: 44; Issue: 5 Linguagem: Inglês

10.1097/01.cot.0000824216.96040.5b

1548-4688

Valerie Neff Newitt,

Pain Management and Placebo Effect

research; researching: research; researchingElizabeth Brem, MD, Assistant Clinical Professor of Medicine at University of California, Irvine (UCI), has a way about her that finds favor among students—hematology fellows named her 2021 Teacher of the Year—and patients, who placed her on a recent Top 20 Physicians for Patient Satisfaction list. But it is diligence in both the clinic and research lab that really defines this emerging physician scientist.Elizabeth Brem, MD: Elizabeth Brem, MD“I think we're in an era of creativity wherein researchers are starting to think outside the box,” Brem told Oncology Times. “For a long time, we depended on status quo—treatments that were effective so we just accepted them for what they were. But now we are adding more things to traditional treatment protocols and seeing if we improve treatment response. We're taking new steps to work out the mechanisms and, at the same time, we're moving away from harsh chemotherapy.” Originally from Buffalo, NY, this married mother of two young sons graduated from Canisius College in Buffalo. It was actually during these undergraduate days that Brem realized oncology was her rightful path. While working on a college research project exploring things that might cause death in leukemia cells, Brem decided to enroll in a summer research program at Roswell Park Comprehensive Cancer Center, the first in the U.S., where she was introduced to the lab of Myron Czuczman, MD. “The investigators not only had a lab, but also did a lot of early-phase clinical trials. And for some reason, they let this crazy college student go to clinic with them,” Brem added with a chuckle. “I was exposed to malignant hematology—the entire bench-to-bedside concept. I was pipetting things in a lab one moment, then seeing patients enrolled in clinical trials the next. It was also this really early look into the doctor-patient relationship in oncology—the frequency of seeing patients, the life-and-death nature of it all, the relationship with the families—that made oncology seem unique from all other areas of medicine.” She continued working on projects in the Czuczman lab while a medical student at SUNY Buffalo. Throughout her training period, Brem continued a hobby that stays with her to this day—ballet dancing. “I have danced ballet since the age of 6 and never stopped,” she said. “I love performing and did pre-professional dance programs and a lot of musical theater. In college, I majored in biochemistry and minored in theater.” Even during training in Boston, she was able to perform with a group called OnStage Dance Company. Her dance résumé includes full-scale productions of The Nutcracker, Giselle, and Cinderella. Here, she expanded her horizon with jazz, contemporary, and even a Bollywood piece, “...which was some of the most fun I've had on stage,” she said. Exploring New Drug Combinations After the curtain dropped on medical school, Brem went to Harvard-affiliated Beth Israel Deaconess Medical Center for an internship, residency, and fellowship. In 2016, she made her way to UCI where she continues some of the research work she started back in Boston, as well as other projects. “As a resident and fellow, I focused on the BCL2 family of proteins and explored how to utilize them as a therapeutic target and how they might play a role in resistance to therapies,” said Brem of prior work underlying a current project. “Now, one clinical trial I am involved with is looking at adding a statin to the drug called venetoclax for use in CLL and AML. We chose to study these two kinds of leukemia because venetoclax is FDA-approved for use with CLL and AML.” Brem noted there are other diseases where it seems to have efficacy, as well, even though it is not yet FDA-approved in those areas. The researchers' hypothesis suggests “...patients on this medication, and other medications in this class, might attenuate other members of the BCL2 families and derive better responses to medications like venetoclax,” said Brem. “We have treated four patients so far in this Phase I clinical trial, and we just got the approval for dose escalation—a move onto the next dose of pitavastatin. If it's tolerated and we see signs of efficacy that it might work better with the statin medicine, we'll move this forward to a Phase II trial.” While other more common cholesterol drugs, such as atorvastatin and rosuvastatin, were considered for the trial, pitavastatin was chosen because it appeared to have the fewest interactions with other drugs and because it seemed to perform best for this purpose while still in a preliminary laboratory setting. Ultimately, said Brem, “It would be wonderful if we had a drug that was easily available, well-tolerated, and easy to add to existing therapies to improve patient responses to anti-cancer drugs. That's our hope.” A Focus on Older Patients Another clinical trial Brem is working on is SWOG Trial S1918. “We are looking at adding a drug called oral azacitidine to standard chemotherapy in patients 75 and older to see if this improves responses compared to chemotherapy alone,” she explained, noting that information from prior studies suggested azacitidine might work in many different subtypes of B-cell lymphoma. “A very exciting aspect of this trial is we are going to be doing various geriatric assessments. We want to see if more treatment affects older people's functioning. Do we cure them, but give them more side effects? Or, conversely, do the people who get more treatment do better overall?” Brem asked, theoretically. “We are incorporating a lot of assessments because we really don't know a lot about older patients with diffuse large B-cell lymphoma. Even though it's a common disease in older patients, they are often excluded from studies due to their age.” Brem noted the National Cancer Institute rightfully has been pushing for more trials with older patients. “When designing the trial, we put in some extra safety parameters that might not have been included for another population. There was a lot of discussion on which assessments to do, how to use them; there was a lot of discussion about the finer details. But there was also a lot of support for the overall concept.” The research team expects to see some decline in patients consistent with other patient populations as well, Brem admitted. “For example, after patients are treated for lymphoma, some have cognitive issues for quite awhile, even after they've finished treatment. I think we will see that phenomenon. But I do not think we will see a dramatic difference between patients getting extra medication and those just getting standard chemotherapy. “My hope is we can make a therapeutic difference for older patients by finding a successful combination of therapies and improve outcomes,” Brem declared. “And because of the geriatric assessments, I hope there will be something to gain in new understanding going forward, regardless of the outcome of the primary endpoint.” Imagining the Future Awaiting the results of clinical trials and translating the findings into clinical practice can take years. However, Brem anticipates what lies ahead, already having seen what a difference such research can make. “As I mentioned, the BCL2 family of proteins was my first experience where I learned about something early on then saw it change patient care,” she said. “I cannot claim to have had a role in that; one of the early drugs that targeted BCL2 that I used in the lab didn't make it to the clinic. But I learned from people who were instrumentally involved in trials that led to getting venetoclax approved in different kinds of leukemia and which is now used in multiple types of blood disorders. I saw the concept evolve.” Brem is optimistic about the future of oncology, because “...we think about things differently today,” she said. “We develop drugs differently, we explore creative combinations based on the biology, and we see less and less chemotherapy being used. In fact, in some diseases that I treat, like CLL for example, we almost never use chemotherapy anymore. That's been a big change over the last 5-7 years.” Indeed, Brem has some patients with slow-growing leukemias and lymphomas for whom she advises a “wait and watch” plan of action. “I tell them there are a number of reasons to wait. In addition to the fact that there is no evidence that immediate treatment will help them live longer, I explain things are progressing so quickly that in 5 years we may have a new, more effective treatment,” said Brem. “The good news is we are using more oral drugs. We are using more drugs that harness patients' own immune systems to get rid of cancer,” she recapped. “Because of the new ways researchers are thinking about attacking these diseases, we are about to see a paradigm shift in the way we treat many cancers compared to just a few short years ago. It's a very exciting time.” Valerie Neff Newitt is a contributing writer.