Verastem’s duvelisib, which has Fast Track designation for relapsed or refractory chronic lymphocytic leukaemia (CLL), has been submitted for FDA approval to treat relapsed or refractory CLL and small lymphocytic lymphoma (SLL) patients who have received at least one prior therapy. If approved, duvelisib will become the first PI3K inhibitor to demonstrate efficacy as a monotherapy in this subgroup.

Importantly, in the Phase III DUO trial, the oral drug improved progression-free survival (PFS) by 3.7 months over the comparator ofatumumab (Arzerra) (hazard ratio [HR] 0.41; p = 0.001) in a subset of patients with the high-risk 17p deletion, who are less likely to respond to standard treatments and have a poorer prognosis. However, duvelisib will not be a game-changer for relapsed/refractory CLL and 17p deletion patients, given the competitiveness of the market.

Duvelisib’s main competitors, ibrutinib (Imbruvica) and idelalisib (Zydelig), have been available for relapsed/refractory CLL since 2014. The first-in-class Bruton’s tyrosine kinase (BTK) inhibitor Imbruvica possesses impressive efficacy and safety profiles, whereas the PI3Kδ inhibitor Zydelig, which shares a mechanism of action with duvelisib, has the benefit of first-to-market advantage. AbbVie’s venetoclax (Venclexta) is also gaining usage in the relapsed/refractory setting, where its usage in combination with rituximab (Rituxan) is a category 1 recommendation in NCCN guidelines for patients without 17p deletions.

Duvelisib’s drawbacks

Apart from the competitive market duvelisib is entering, the drug itself carries toxicity concerns and its long development journey has led to questions about the relevance of its pivotal trial design.

A number of side effects were reported with duvelisib in the DUO clinical trial. The most severe adverse events (grade 3 or worse) were neutropenia (30%), anaemia (13%), diarrhoea (15%), pneumonia (14%) and colitis (12%). In 5% of patients, diarrhea or colitis led to treatment discontinuation. The substantial adverse events that were associated with duvelisib represent yet another drawback that will discourage physicians from prescribing duvelisib; therefore, its usage may be limited to salvage settings.

While there are ongoing Phase I and II investigator-sponsored trials exploring duvelisib in combination with Rituxan or chemotherapy, duvelisib’s lack of tolerability as a monotherapy limits its possible use in combination. Another major limitation is the design of the randomized DUO Phase III clinical trial, which excluded any patient with prior treatment involving a PI3K or BTK inhibitor. This has significant implications for the eligible patient pool, given that Imbruvica is increasingly moving to front-line therapy and thus may limit duvelisib’s use to patients who are Imbruvica-naive.

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Duvelisib’s long development road means the treatment algorithms have shifted since the DUO trial began and, as such, the enrolled patient population may not be as relevant as it was at the initiation of the trial. What’s more, the relevance of Arzerra as a comparator arm in the study is questionable given its declining usage in the relapsed/refractory setting, particularly outside of the US.

Despite its challenges, an advantage duvelisib has is its convenience as an oral agent in monotherapy as opposed to the combined administration of the oral drug Zydelig with Rituxan, which must be given either subcutaneously or intravenously. Furthermore, duvelisib’s once daily oral administration adds another layer of convenience over the twice-a-day regimen associated with Zydelig. In addition, as a dual δ/γ-specific inhibitor of the PI3K enzyme, duvelisib’s inhibition of multiple isoforms may prove more efficacious compared to Zydelig’s single inhibition of the PI3Kδ protein.

It remains to be seen whether duvelisib stands much of a chance in the future, especially given its many shortcomings and fierce competition in the field, but its prospects appear relatively weak.