Just because a cancer drug is approved by the FDA does not mean its therapeutic benefit is completely understood. Improving outcomes and minimizing side effects of a drug often requires using the drug in different doses or in combination with other drugs.
According to data presented at the 2020 ASCO annual meeting, this is especially so in leukemia, a blood cancer that is remarkably complex, because it is often associated with genetic mutations or alterations.
Rachel J. Cook, MD, Associate Professor of Medicine, School of Medicine, Oregon Health & Science University, Portland, discussed the role of oral targeted therapies in the treatment of leukemia, and the challenges that are inherent in making the best selection for the individualized patient.
She presented 3 clinical trials with different targeted therapies to highlight the role of these studies in exploring the right drugs and dosing for patients with different types of leukemia.
Ivosidenib, Venetoclax, and Azacitidine in Leukemia with IDH1 Mutation
The first example was an early study—a phase 1b/2 clinical trial that examined the combination of Tibsovo (ivosidenib) and Venclexta (venetoclax) with addition of Vidaza (azacitidine) in later dosing groups. The study used a design that allowed for the evaluation of the interactions among these drugs (how they affect each other), as well as data related to their pharmacokinetics (what the body does with a drug) and pharmacodynamics (what a drug does to the body).
“As we move deeper into the era of targeted therapies, this type of study design will be important,” said Dr. Cook.
“Evaluating overlapping toxicities [side effects] and drug levels of therapeutic agents, as well as supportive care medicines will be required to avoid drug and dosing errors.”
The study’s findings showed that the addition of ivosidenib caused a decrease in the concentration levels of venetoclax by approximately 50%, meaning that the activity of venetoclax is being reduced when combined with ivosidenib.
Although the ramifications on the benefit of the drugs in this case are less clear, said Dr. Cook, it drives home the point that drug interactions require careful attention, particularly in patients with leukemia who are receiving multiple cancer drugs, as well as multiple supportive and prophylactic (preventive) medicines.
Moreover, in patients with widely varied disease biology, Dr. Cook said, it can be difficult to determine the driving force behind the cancer’s response to a drug. When examining the results for survival, the breakdown by disease type is just as important as the treatment group in this specific study.
“This study demonstrates the complexity of novel drug therapies and the challenge of working with a cohort defined by a single mutation,” she explained.
“While every patient was IDH1-positive, this well-described patient cohort with widely varied molecular profiles reinforces that every patient is actually an N-of-1 experiment,” she said, meaning that every single patient represents all the patients in the study.
Enasidenib plus Azacitidine in AML with IDH2 Mutation
The second study included patients with newly diagnosed acute myeloid leukemia (AML) and IDH2 mutation. The patients were randomized into 2 groups—1 group received azacitidine alone and the other group received azacitidine plus Idhifa (enasidenib).
The average age of the patients in the study was 75 years, said Dr. Cook, capturing a true older adult population that was not fit to receive standard first-line therapy for this type of AML.
The combination of enasidenib plus azacitidine significantly improved the cancer’s overall response to therapy compared with azacitidine alone. It is interesting, said Dr. Cook, that the slower response to treatment with enasidenib required an average of 5.5 cycles of treatment to reach a complete response (no sign of cancer) compared with the standard 4 cycles of azacitidine therapy when used alone.
Therefore, she emphasized, “It’s important that decisions to change therapies are not made prematurely.”
The level of the cancer’s response to therapy also improved with the combination of enasidenib plus azacitidine, and the degree of IDH2 mutation clearance correlated with an increased chance of complete response to treatment. Of note, said Dr. Cook, although complete response was associated with improved survival, the overall survival was the same in both groups.
“It appears that we are starting to enter the realm of multiple myeloma, where we finally have effective drugs for AML, but are still learning how to optimize their sequencing,” said Dr. Cook. “Patients may respond to a drug at different stages of their disease, making demonstration of a survival benefit more difficult,” she added.
“Hopefully, with increasing molecular data and patient characteristics, we can identify patients earlier who are most likely to benefit from targeted therapy combinations for improved response rates and overall survival,” Dr. Cook added.
Study with 3 Starting Doses of Ponatinib for CML
Finally, a study of patients with chronic myelogenous leukemia (CML) shows the importance of dose modifications to minimize toxicity and maximize the benefit of therapy. This study examined 3 different initial doses of Iclusig (ponatinib) in patients with chronic-phase CML who could not tolerate or whose cancer was resistant to treatment with at least 2 tyrosine kinase inhibitors or who had T315I gene mutations.
According to Dr. Cook, this study design demonstrates the potential complexity in the treatment of patients with CML.
“Even with only 1 marker to follow and 1 drug, learning to match the drug, treat the disease, and minimize the risks to the patient is not straightforward,” she said. “It appears promising for patients with a T315I mutation that they may have a better chance of obtaining a deeper remission with higher initial doses of ponatinib.”
The results of this study will help doctors to balance the risks of side effects with the chance of benefit, while making individualized treatment decisions, Dr. Cook said.
“Because overall survival is high in chronic-phase CML, it becomes even more important to maximize quality of life by minimizing toxicity and risks of therapy. Ideally, each patient will be exposed to just enough dosing and no more,” she concluded.