TERZO Trial Seeks to Validate Duvelisib as an Effective Targeted Treatment in TFH Nodal T-Cell Lymphoma

The phase 3 TERZO trial (NCT06522737) seeks to build upon prior findings from the phase 2 PRIMO study (NCT03372057), which demonstrated antitumor activity and a generally tolerable safety profile with the dual PI3K-δ and -γ inhibitor duvelisib (Copiktra) in patients with peripheral T-cell lymphoma (PTCL), with the ultimate goal of regulatory approval, according to Christopher P. Fox, MBChB(Hons), PhD, FRCP, FRCPath.1 If successful, this research would represent substantial progress toward incorporating more targeted interventions into a historically limited treatment arsenal, Fox emphasized in an interview with OncLive®.

In January 2023, the European Commission granted orphan drug designation to duvelisib for the treatment of adult patients with PTCL based on findings from the PRIMO trial. Previously reported data from PRIMO demonstrated an overall response rate of 48% and a complete response rate of 33.3% with duvelisib (n = 123).2 Duvelisib was also well tolerated, with a safety profile consistent with that observed in prior studies of the agent.

“For investigators and oncologists who treat patients with PTCL, recognizing that T follicular helper [TFH] is a unique biological entity for which the TERZO study was designed [to include], progression-free survival [PFS] superiority [with duvelisib vs standard chemotherapy] would be highly meaningful and would hopefully lead to an approval,” Fox stated. “It’d be a first step towards a biologically-targeted intervention prolonging PFS in the relapsed/refractory setting, which would be significant.”

In the interview, Fox discussed duvelisib’s key mechanism of action in PTCL, discussed prior data supporting the initiation of the TERZO trial, and underscored how the unmet need for effective therapies in PTCL justifies the agent’s continued development despite challenges with developing the PI3K inhibitor class in other lymphoma subtypes.

Fox is a clinical professor of hematology in the Faculty of Medicine and Health Sciences at the University of Nottingham Centre for Cancer Sciences, Academic Unit of Translational Medical Sciences, School of Medicine; he also serves as an honorary consultant hematologist at Nottingham University Hospitals NHS Trust, in England.

OncLive: What do preclinical data indicate about the mechanism of action of duvelisib in PTCL?

Fox: Duvelisib is an orally administered inhibitor of PI3K. This is a lipid kinase, an important kinase for signal transduction within the cell, and it has pleiotropic effects on cancer cell survival, proliferation, and differentiation. PI3K has 4 subunits: α, β, δ, and γ. Duvelisib inhibits specifically the δ and γ subunits, which are preferentially expressed in leukocytes. That [explains] its more targeted mechanism of action.

The preclinical data supporting the mechanism of action and the potential efficacy of duvelisib in hematological malignancies, including PTCL, are strong. There’s a wealth of evidence that inhibiting PI3K and its different subunits can have anticancer activity both in cell lines and in animal models. There are also persuasive data showing that by inhibiting the δ and γ duvelisib exerts a significant anticancer effect through several different mechanisms.

Given the high median relative dose intensity observed with duvelisib in the PRIMO study, do you anticipate the same level of dose intensity in the ongoing TERZO trial?

We observed a good median dose intensity of duvelisib in the early-phase PRIMO study. The dosing schedule was designed to [start with] a higher dose of 75 mg twice a day for the first 2 cycles of treatment to maximize tumor control, before dropping to 25 mg twice a day from cycle 3 onward. The rationale here was to mitigate against later immune-mediated toxicities [commonly associated] with duvelisib and this class of agents. This translated into good dose intensity, particularly early in [the treatment course], which is important for tumor control. We hypothesize that this dosing schedule will deliver good adherence and good dose intensity within the TERZO study, but that remains to be seen.

How might the agent’s unique dosing schedule affect its adverse effect (AE) profile compared with standard chemotherapy?

Within the phase 2 study, we saw an AE profile with duvelisib that was generally consistent with that of other PI3K inhibitors, with a potentially lower frequency of severe immune-mediated toxicities. The data so far are supportive of taking this dosing schedule into the phase 3 [trial], and then we’ll be able to compare [duvelisib] in a randomized fashion vs standard chemotherapy and make a clearer judgement as to whether the PI3K inhibitor is putting patients more at risk of these immune-mediated AEs than we would see with standard therapy.

A significant percentage of patients in PRIMO were able to proceed to transplant after receiving duvelisib. Pending the agent’s approval, how might duvelisib be integrated into clinical practice, particularly based on whether patients are good candidates for transplant?

The goal of therapy, particularly when we’re considering long-term remission and cure, is to deliver patients to [the point of] stem cell transplantation, which maximizes their chance of achieving long-term remission. For patients with relapsed/refractory PTCL—and those with the TFH [phenotype], including angioimmunoblastic T-cell lymphoma—who would be fit enough to undergo allogeneic transplant and have a suitable donor, [transplant] remains the goal of any treatment strategy. That will be an important strategy for a subset of patients. However, many older, less fit patients wouldn’t be considered suitable candidates for transplant, in which case the continuation of duvelisib would probably be the best therapeutic strategy.

In December 2021, the indication for duvelisib in follicular lymphoma was voluntarily withdrawn from the United States market. Do you think this past decision will affect duvelisib’s ongoing development?

We’ve seen several PI3K inhibitors targeting the different subunits of PI3K, so that has relevance to the efficacy and toxicity profile [of duvelisib], but we must recognize that the clinical development of this class of agents has a checkered history. This comes down to the balance between efficacy and toxicity. PI3K inhibitors display efficacy across a range of B- and T-cell malignancies, but their delivery and developmental success has been hampered by some of these toxicities, including infections and immune-mediated toxicities.

In follicular lymphoma or chronic lymphocytic leukemia [CLL], for example, the relative benefits of PI3K inhibition have not been countered by significant toxicities. [However, the development of these agents was] accompanied by the development of many more effective agents for CLL and follicular lymphoma, so the risk/benefit profile of PI3K inhibitors in those diseases started to be less favorable. Ultimately, that’s why [some PI3K inhibitors] were withdrawn from the market.

In PTCL, where we have few effective agents approved by the FDA or in Europe and the United Kingdom, there’s a greater need for effective therapies. [Accordingly,] there may be a broader acceptance of managing and monitoring for the accompanying toxicities. PTCL is a different disease with a different risk/benefit profile, but studying duvelisib in a randomized trial [for this disease] is clearly the right approach.

What are the design and primary objective of the ongoing TERZO trial?3

The TERZO trial is an open-label, randomized, controlled trial investigating duvelisib vs investigator’s choice of either gemcitabine or bendamustine, which are the established standard of care [SOC] for patients with relapsed/refractory PTCL. The TERZO trial will focus on patients with the TFH subtype of nodal T-cell lymphoma, which constitutes a significant proportion of patients with PTCL. This subtype can be readily identified using a range of now well-established immunohistochemical markers, which will be part of the screening process.

The study’s primary objective is to show an improvement in PFS with duvelisib over standard chemotherapy. It’s important to investigate this in a randomized setting with a multicenter approach. Because of the rarity of this disease, we need international collaboration to address this question.

Do you foresee any barriers to enrollment or other challenges for conducting this trial?

For patients with relapsed/refractory PTCL, many centers in different countries would regard a clinical trial as a SOC, given the poor outcomes for patients who are given conventional treatments. Clinical trials are always attractive options for patients with PTCL. Barriers to recruitment will therefore come down to patient- and center-related factors. Patients may not be able to travel to a center that has the trial open. Some centers may also choose to preferentially use stem cell transplantation as a treatment option, [although] that’s typically [given to] a minority of patients.

In terms of trial eligibility, aside from defining the TFH subtype, which was [the population in which] most efficacy was seen in PRIMO, the inclusion and exclusion criteria are generally pragmatic. The concept of the TERZO trial is to include as many patients as possible within the safety constraints of a clinical trial with an investigational drug. I hope we don’t see too many barriers to recruitment beyond the usual access issues.

How might positive results from the TERZO trial affect the future development of duvelisib for relapsed/refractory PTCL?

[TERZO] is a study with regulatory intent by design. If the trial is positive and we see a statistically significant PFS benefit with duvelisib [over chemotherapy] for patients with relapsed/refractory [nodal T-cell lymphoma] and the TFH [phenotype], that would be practice changing. [As long as] the toxicity profile was deemed acceptable and within the limits of what we understand PI3K inhibitors to deliver clinically, a superior PFS [with duvelisib] would be significant and [could lead to an approval.]

References

1. Cwynarski K, Domenech ED, Sidransky D, Bentur OS, Zinzani PL. A multicenter, open-label, phase 3, randomized controlled trial of duvelisib versus investigator’s choice of gemcitabine or bendamustine in patients with relapsed/refractory nodal T cell lymphoma with T follicular helper phenotype. Blood. 2024;144(suppl 1):3074.1. doi:10.1182/blood-2024-203290
2. Mehta-Shah N, Zinzani PL, Jacobsen ED, et al. Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma: final results from the phase 2 PRIMO trial. Blood. 2024;144(suppl 1):3061. doi:10.1182/blood-2024-203577
3. A study of duvelisib versus gemcitabine or bendamustine in participants with relapsed/refractory nodal T cell lymphoma with T follicular helper (TFH) phenotype (TERZO). ClinicalTrials.gov. Updated February 4, 2025. Accessed February 20, 2025. https://clinicaltrials.gov/study/NCT06522737