VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).
The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.
And 47% of the responses occurred by the first assessment on day 1 of cycle 3.
“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.
“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”
Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.
Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.
In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.
So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.
Patient demographics
Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”
She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.
“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.
Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.
Response
Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.
The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.
One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.
“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”
The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.
The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.
Adverse events
The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.
Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).
Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).
The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.
“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”
Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.
Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.
*Information in the abstract differs from that presented at the meeting.