Duvelisib for Relapsed or Refractory CLL/SLL

January 22, 2019

The FDA has approved duvelisib (Copiktra, Verastem) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies.1 CLL and SLL are types of non-Hodgkin lymphoma.2 Duvelisib is an oral phosphatidylinositol 3-kinase (PI3K) inhibitor with dual activity against delta and gamma kinases, which are expressed in malignancies like CLL and SLL. Inhibition of PI3K reduces tumor cell proliferation, and decreases differentiation/migration of tumor support cells. Duvelisib also inhibits B-cell receptor signaling pathways, T cell migration, and macrophage polarization.3

Efficacy

Approval for CLL and SLL came from the clinical trial DUO; an open-label two-arm randomized phase 3 superiority trial designed to evaluate the efficacy and safety of duvelisib compared to ofatumumab in patients diagnosed with relapsed or refractory CLL/SLL.4 In the trial, 313 patients were randomly assigned to receive duvelisib 25 mg by mouth twice daily or intravenous ofatumumab at an initial dose of 300 mg, followed a week later by 2,000 mg once weekly for 7 doses, then 2,000 mg once every 4 weeks for 4 doses.1

Median progression-free survival was significantly longer in the duvelisib group-13.3 months versus 9.9 months (hazard ratio [HR] = 0.52, p<0.0001). The overall response rate for duvelisib was significantly higher than that of ofatumumab (73.8% versus 45.3%; p < 0.0001). Median OS was not reached on either treatment arm with a 12-month probability of survival of 86% (HR = 0.99; 95% confidence interval: 0.65, 1.50).5

Side Effects

The most common hematologic adverse effects with duvelisib are neutropenia (33%), anemia (23%), and thrombocytopenia (15%). The most common nonhematologic adverse effects are diarrhea (51%), pyrexia (29%), nausea (37%), cough (21%), pneumonia (18%), constipation (17%), upper respiratory tract infection (16%), and vomiting (15%).5

Duvelisib has black-box warnings for dermatologic events, gastrointestinal toxicity, infection risk, and pulmonary toxicity. For dermatologic events with a severe cutaneous reaction, median time to onset was 3 months and typically lasted for 1 month. Stopping medication and giving supportive corticosteroids and/or antihistamines is advised.3

Diarrhea or colitis typically occurs in the first 8 months of therapy and monitoring should be done weekly for these side effects. Supportive management with antidiarrheals, corticosteroids, and treatment interruption, dose reduction, or discontinuation is advised.3

The most common serious infections were pneumonia, sepsis, and lower respiratory infections; most (75%) occur within 6 months. Treat preexisting infections before therapy initiation. If infections develop while on therapy, withholding duvelisib is recommended until infection resolves. Pneumocystis jirovecii pneumonia (PCP) and Cytomegalovirus have been reported; prophylaxis for both during therapy is suggested.3

If patients develop pulmonary toxicity, withholding treatment is advised until determination of infectious or non-infectious pneumonitis.3

Duvelisib is a part of the Risk Evaluation and Mitigation Strategy (REMS) program because of the black-box warnings. Providers receive a letter about the risks and are encouraged to give patients with a wallet care with safety information.6

Dosing and Cost

Recommended dosing of duvelisib is 25 mg orally twice daily, with or without food.7 If a dose is missed by fewer than 6 hours, administer it immediately. If the delay is more than 6 hours, administer the next dose at usual time. Pricing is expected to be more than $15,000 for sixty 25 mg capsules.

Kathleen Golebiewski is a PharmD Candidate at the University of Connecticut School of Pharmacy, Class of 2019. Lisa Holle, PharmD, BCOP, FHOPA, is associate clinical professor at the UConn School of Pharmacy, Storrs, CT.

Page 2: References

References

1. Approved Drugs - Duvelisib (COPIKTRA, Verastem, Inc.) for Adult Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). FDA Home Page, Center for Drug Evaluation and Research. Available at https://bit.ly/2xTYUNr. Accessed Dec. 5, 2018.

2. NCI Dictionary of Cancer Terms.. Available at https://bit.ly/2FZST8Z. Accessed Nov. 25, 2018.

3. Lexicomp. Duvelisib. Wolters Kluwer Heath, Inc. Riverwoods, IL. Available at http://online.lexi.com. Accessed Nov. 16 and 26, 20184. Clinicaltrials.gov.  A Phase 3 Study of duvelisib versus ofatumumab in patients with relapsed or refractory CLL/SLL (DUO). (Clinicaltrials.gov Identifier NCT02004522). Available at https://bit.ly/2KVv4OF. Accessed Dec. 5, 2018.

5. Flinn IW, et al. The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL. Blood, blood-2018-05-850461. Accessed November 16 and 26, 2018. https://doi.org/10.1182/blood-2018-05-850461.

6. Approved Risk Evaluation and Mitigation Strategies (REMS). Sept. 24, 2018. Available at https://bit.ly/2RIhFvC. Accessed Nov. 26, 2018.

7. Package Insert. Copiktra (duvelisib)  Verastem, Inc., Needham, MA.; September 2018.

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