Crossover to Duvelisib Feasible in Patients With CLL

Matthew S. Davids, MD, MMSc

Duvelisib (Copiktra) monotherapy achieved robust and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to updated data presented at the 2018 ASH Annual Meeting.

The phase III DUO study compared single-agent duvelisib with ofatumumab (Arzerra) monotherapy, and showed a clear survival advantage to the PI3K inhibitor. In this updated analysis, patients who experienced disease progression on ofatumumab were crossed over to duvelisib.

Median progression-free survival (PFS) was 15 months on duvelisib post-crossover compared with 9 months for the patients treated with ofatumumab pre-crossover. This difference was even more pronounced in patients with del(17p) (n = 20), who had a PFS of 17 months (95% CI, 9-21) on duvelisib post-crossover compared with a PFS of 8 months on ofatumumab pre-crossover. The overall response rate in the patients treated with duvelisib was 77% compared with 29% in those treated with ofatumumab.

The most common severe hematologic adverse events (AEs) experienced by those who received duvelisib were neutropenia (23%) and thrombocytopenia (4%), while the most common severe nonhematologic AEs included diarrhea (21%), pneumonia (12%), colitis (11%), lipase increased (7%), acute renal failure (6%), and bronchitis (4%), rash (4%), and sepsis (4%).

As a result of the initial phase III study the FDA approved duvelisib in September 2018 for the treatment of patients with relapsed/refractory CLL or relapsed/refractory follicular lymphoma. The CLL indication is a standard approval and the follicular lymphoma indication is an accelerated approval contingent on the results of a confirmatory trial. Both indications are for the treatment of patients who have received at least 2 prior therapies.

In DUO, duvelisib reduced the risk of disease progression or death by 60% versus ofatumumab in patients with relapsed/refractory CLL who had received at least 2 prior lines of therapy. The median PFS was 16.4 months with duvelisib versus 9.1 months with ofatumumab (HR, 0.40).

OncLive: Please provide some background to the DUO trial.

What were the results presented at the 2018 ASH Annual Meeting?

In an interview with OncLive at the 2018 ASH Annual Meeting, Matthew S. Davids, MD, MMSc, the Associate Director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, discussed the clinical implications of this trial in patients with CLL.Davids: The DUO trial looked at the use of duvelisib in patients with CLL. Duvelisib is a delta-gama PI3K inhibitor that is being compared in this study to ofatumumab, a CD20-targeted monoclonal antibody. In the initial results, there was a clear advantage to duvelisib over ofatumumab. These data led to the FDA approval of the drug in September 2018.The design of the DUO trial included a crossover portion, so patients treated with ofatumumab who experienced disease progression could then move on to duvelisib. At this meeting, I presented the updated data of the 90 patients who crossed over to duvelisib monotherapy. The patients who received duvelisib tended to do well in general. We saw responses in about three-quarters of the patients. The PFS rates were comparable to what we saw in the earlier parts of the study. There did not appear to be any detriment to being treated with ofatumumab first in terms of duvelisib response. The drug was generally well tolerated for most patients, although there are some AEs that need to be monitored closely, such as diarrhea and colitis.

What are the key takeaways from the trial?

What are some unanswered questions with duvelisib?

One of the biggest questions we had was whether patients with different molecular markers would respond differently. We were particularly curious about the patients with the high-risk del(17p) abnormality. Fortunately, both PFS and response rates were very similar compared to the larger group.Duvelisib appears to be an effective treatment option for relapsed CLL after 2 or more lines of therapy. Patients may receive a drug like ofatumumab first and still do very well on duvelisib once they progress. Although we have many different options in CLL, for a disease that is incurable for most patients, it is helpful to make new treatment options like this available. Going forward, we know the activity of this drug as a single agent. One of the things I would be excited to see is what this drug can do in combination with other agents. We have been running a frontline setting of duvelisib with FCR, and we are testing it with venetoclax in relapsed/refractory patients.

Davids, MS, Kuss BJ, Hillmen P, et al. The efficacy and safety of duvelisib following disease progression on ofatumumab in patients with relapsed/refractory CLL or SLL: updated results from the DUO crossover extension study. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 3140.