In a potentially significant stride in the treatment of patients with indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma, a new drug, duvelisib, unlike previous therapies, appears to be clinically beneficial and have a well-characterized and manageable safety profile among individuals with double refractory follicular lymphoma, small lymphocytic lymphoma, or marginal zone lymphoma (Hematol Oncol 2017; doi:10.1002/hon.2437_57).
Long-term follow-up data from the DYNAMO study, which met its primary endpoint of overall response rate (ORR; p=0.0001) at the final analysis, was presented during the International Congress on Malignant Lymphoma in Lugano, Switzerland.
“Unfortunately, there are no curative therapies for low-grade lymphoma and recurrence is common after remission,” said Ian Flinn, MD, PhD, primary investigator of the study and Director of the Blood Cancer Research Program at Sarah Cannon. “Consequently, many different approaches are needed over the lifespan of a patient. The hope is that this drug will add to our armamentarium for treating patients with low-grade lymphoma.”
Duvelisib is an oral treatment targeting enzymes—specifically, PI3K-delta and PI3K-gamma—that promote the growth and survival of cancerous B cells and T cells.
“[Duvelisib] belongs to a new class of drugs that will play a major role in the management of indolent lymphomas,” said Adan Rios, MD, Associate Professor in the Division of Oncology at the McGovern Medical School at The University of Texas Health Science Center at Houston and Memorial Hermann-Texas Medical Center.
It's another way to supplement the current standard of treatment of these disorders, he continued. The previous standard cancer treatments and the ones in current use had “deleterious effects that tend to be permanent. I don't think that's the case with the agents we're discussing here.
“These are drugs that interfere with metabolic pathways. By doing so, their action, in a sense, is reversible,” explained Rios. “That's a tremendous advantage over the effects of some of the chemotherapeutic agents we currently use which, once given, have effects that are essentially irreversible.
“I think this is one of the most important and dramatic changes offered by these new types of agents.” Previously, he noted, “we've relied so much on cutting, burning, and poisoning” the language that's dominated the way we think about cancer. These words are about “war” and imply destruction.”
DYNAMO (NCT01882803) is a phase II, single-arm study, which evaluated the efficacy and safety of duvelisib 25 mg twice daily as monotherapy in 129 iNHL patients, including follicular lymphoma (n=83), small lymphocytic lymphoma (SLL) (n=28), and marginal zone lymphoma (n=18) whose disease has progressed and are refractory to rituximab and either chemotherapy or radioimmunotherapy.
The primary endpoint of the study was ORR as assessed by an independent review committee. The presentation focused on the subsets of patients with follicular lymphoma or SLL who were enrolled in DYNAMO. With a median of 18 months of follow-up, the long-term data remains consistent with the primary analysis.
Of the 83 patients with double-refractory follicular lymphoma enrolled in DYNAMO (median three prior anticancer regimens [range 1-10]), 36 responded, which included one (1%) complete response and 35 (42%) partial responses, for an ORR of 43 percent as determined by an independent review committee.
Responses generally occurred shortly after the start of treatment (median 2 months). Notably, 83 percent of evaluable patients with follicular lymphoma treated with duvelisib had a reduction in the size of their target lymph nodes. Median duration of response was 7.9 months, median progression-free survival was 8.3 months, and median overall survival was 27.8 months.
Of the 28 patients with double-refractory SLL enrolled in DYNAMO (median three prior anticancer regimens [range 1-18]), 19 responded, all of which were PRs, for an ORR of 68 percent. Responses generally occurred shortly after the start of treatment (median 2 months). Importantly, 100 percent of evaluable patients with double-refractory disease treated with duvelisib had a reduction in the size of their target lymph nodes. With a median time on duvelisib of 12 months, median duration of response was 10.1 months, median progression-free survival was 11.7 months, and median overall survival was 28.9 months.
“We believe that oral duvelisib has the potential to be an important new treatment option for lymphoma patients,” Pier Luigi Zinzani, MD, PhD, Associate Professor of Hematology at the Institute of Haematology at the University of Bologna and an investigator participating in the study, commented in a statement. “What I find particularly encouraging are the responses we saw in patients with double-refractory disease, a population with few treatment options left. The data we are presenting continue to demonstrate that duvelisib monotherapy can achieve meaningful and durable responses.”
The safety profile of duvelisib monotherapy remains consistent with what has been previously reported in iNHL and other advanced hematologic malignancies.
In these double-refractory follicular lymphoma patients, the most common grade ≥3 hematologic adverse events were neutropenia (22%), anemia (13%), and thrombocytopenia (9%). Diarrhea was the most frequently reported nonhematologic adverse event (47%; 16% Grade ≥ 3).
As expected in a heavily pretreated and refractory patient population, severe infections were observed (20%). Pneumonitis and colitis remained relatively uncommon (each 5%). Treatment discontinuations attributed to severe adverse events were infrequent, suggesting that these events were generally manageable.
In double-refractory SLL patients, the most common grade ≥3 hematologic adverse events were neutropenia (32%), thrombocytopenia (21%), and anemia (21%). The most frequently reported grade ≥3 nonhematologic adverse events were pneumonia (14%), increases in alanine aminotransferase (7%), aspartate aminotransferase (11%), and diarrhea (11%). Severe infections were observed (36%). Colitis occurred in three (11%) SLL patients. No double-refractory patients experienced pneumonitis. Treatment discontinuations attributed to the most common adverse events were infrequent, suggesting that these events were generally manageable.
“I think we're just really beginning the investigation of this drug; there are a lot of unanswered questions about how to best use it, not only in low-grade lymphoma, but other diseases as well,” said Flinn who is a hematologist/oncologist with Tennessee Oncology in Nashville and Tullahoma, Tenn. For instance, he continued, “do we want to combine this with other therapies, such as with chemo? Are there ways of getting people off the drug and giving them a combo therapy that will allow us, ultimately, to get people off the drug?”
Flinn also noted that study participation was limited to those patients whom had few options and refractory disease, targeting patients who weren't responding to chemotherapy. “Perhaps in the future, the drug could be administered earlier in the course of the disease to produce better outcomes. We look forward to continuing to research these possibilities for patients. The results from DYNAMO are a good starting point.”
Yet, with all its potential promise, the drug's not without possible drawbacks, like side effects, Flinn commented.
“All therapies have side effects, including duvelisib. However, the side effects seen with duvelisib are largely predicable and manageable. The side effect profile is similar to other PI3K inhibitors. Many patients can be restarted at the same or lower dose after holding treatment for brief period, allowing the patient to remain on therapy and continue to derive benefit,” said Flinn.
In the meantime, he said the investigation of the treatment is in its initial stages. “There's a lot of unanswered questions about how to best use it, not only in low-grade lymphoma, but other diseases as well. For instance, we're researching whether this drug would have efficacy in combination with other therapies, such as with chemotherapy.”
Whatever the case, with this therapy, Rios emphasized, “we're not seeing cancer as an enemy, but rather something that needs to be modulated. This approach is bringing a better understanding of the cell/cancer metabolic pathways, and cells survival to the forefront. The incorporation of this knowledge is now creating new classes of agents to treat this disease.”
Chuck Green is a contributing writer.