In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On September 24, 2018, duvelisib (Copiktra) was granted regular approval for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. Duvelisib also received accelerated approval for adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies.^1,2

Supporting Efficacy Data

THE CLL/SLL indication is based on findings in a trial (ClinicalTrials. gov identifier NCT02004522) in which patients with relapsed or refractory CLL or SLL were randomly assigned to receive duvelisib at 25 mg orally twice daily or ofatumumab (Arzerra).² Ofatumumab was given at an initial dose of 300 mg followed 1 week later by 2,000 mg once weekly for 7 doses and then 2,000 mg once every 4 weeks for 4 additional doses. Among 95 patients assigned to duvelisib and 101 assigned to ofatumumab who received at least 2 prior therapies, the estimated median progression-free survival on independent review committee assessment was 16.4 months in the duvelisib group vs 9.1 months in the ofatumumab group (hazard ratio = 0.40, standard error = 0.2). The overall response rate was 78% vs 39%.

The follicular lymphoma indication is based on findings in a single-arm multicenter trial (NCT02204982) in 83 patients with disease refractory to rituximab (Rituxan) and to either chemotherapy or radioimmunotherapy who received duvelisib at 25 mg twice daily. The objective response rate on independent review committee assessment was 42%. Among responders, 43% maintained a response for a minimum of 6 months and 17%, for at least 12 months.

How It Works

DUVELISIB IS an inhibitor of phosphoinositide 3-kinase (PI3K) with inhibitory activity predominantly against PI3K-δ and PI3K-γ isoforms expressed in normal and malignant B cells. It inhibits growth and reduces viability in cell lines derived from malignant B cells and in primary CLL tumor cells.

The agent also inhibits several key cell-signaling pathways, including B-cell receptor signaling and CXCR12-mediated chemotaxis of malignant B cells. In addition, it inhibits CXCL12-induced T-cell migration and macrophage colony-stimulating factor– and interleukin 4–driven M2 polarization of macrophages.

How It Is Used

THE RECOMMENDED dose of duvelisib in the current indications is 25 mg orally twice daily. Patients should receive prophylaxis for Pneumocystis jirovecii pneumonia during treatment. Prophylaxis should be continued after treatment until the absolute CD4-positive T-cell count is greater than 200 cells/μL. Prophylactic antivirals should be considered during treatment to prevent cytomegalovirus infection including cytomegalovirus reactivation. The recommended dose reduction for adverse events is to 15 mg twice daily, with discontinuation of treatment if the lower dose is not tolerated.

Product labeling provides detailed instructions on dose modifications and withholding and discontinuation of treatment for infections, noninfectious diarrhea or colitis, cutaneous reactions, pneumonitis without suspected infectious cause, alanine transaminase (ALT)/aspartate transaminase (AST) elevation, neutropenia, and thrombocytopenia. Treatment should be permanently discontinued for confirmed P jirovecii pneumonia; recurrent grade 3 diarrhea or recurrent colitis of any grade or life-threatening diarrhea or colitis; any severe cutaneous reaction that does not improve, worsens, or recurs and life-threatening cutaneous reactions; any-grade drug reaction with eosinophilia and systemic systems, Stevens-Johnson syndrome, or toxic epidermal necrolysis; recurrent noninfectious pneumonitis or pneumonitis not responding to steroid therapy and grade 3 or life-threatening pneumonitis; and ALT/AST elevation greater than 20 times the upper limit of normal.

Product labeling also provides instructions on concomitant use of duvelisib with CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort), CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole), and CYP3A substrates (eg, aprepitant, budesonide, lovastatin, midazolam).

Safety Profile

SAFETY DATA for duvelisib are from clinical trials including 442 patients with previously treated hematologic malignancies, primarily CLL/SLL (69%) and follicular lymphoma (22%), who received the drug at 25 mg twice daily until unacceptable toxicity or progressive disease.

The most common adverse events of any grade were diarrhea or colitis (50%), neutropenia (34%), rash (31%), fatigue (29%), pyrexia (26%), cough (25%), nausea (24%), upper respiratory infection (21%), pneumonia (21%), musculoskeletal pain (20%), and anemia (20%). The most common grade ≥ 3 adverse events were neutropenia (30%), diarrhea or colitis (23%), pneumonia (15%), anemia (11%), thrombocytopenia (10%), rash (9%), and transaminase elevation (8%).

Serious adverse events occurred in 65% of patients, with the most common being infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%). Adverse events led to treatment discontinuation in 35% of patients, most often due to diarrhea or colitis, infection, and rash. Dose reduction occurred in 24% of patients, most often due to diarrhea or colitis and transaminase elevation. Fatal adverse events within 30 days of the last dose occurred in 36 patients (8%).

Duvelisib has boxed warnings for fatal or serious infections (which occurred in 31% of patients), fatal or serious diarrhea or colitis (18% of patients), fatal or serious cutaneous reactions (5% of patients), and fatal or serious pneumonitis (5% of patients). Duvelisib also carries warnings/precautions for hepatotoxicity, neutropenia, and embryofetal toxicity.

Patients receiving duvelisib therapy should be monitored for signs and symptoms of infection, diarrhea or colitis, pulmonary symptoms and interstitial infiltrates, hepatic function, and blood cell counts. Women should be advised not to breastfeed during treatment with duvelisib. ■

REFERENCES

1. U.S. Food and Drug Administration: Duvelisib (Copiktra, Verastem, Inc) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm621503.htm. Accessed October 2, 2018.

2. Copiktra (duvelisib) capsules prescribing information, Verastem, Inc, September 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf. Accessed November 26, 2018.