Reddy Reviews Paradigm Shifts in CD30-Positive PTCL, Next Steps for Research

The emergence of brentuximab vedotin (Adcetris) plus cyclophosphamide, doxorubicin, and prednisone (CHP) in the treatment armamentarium for advanced peripheral T-cell lymphoma (PTCL) led to a shift in the paradigm for patients with CD30 positivity, according to Nishitha M. Reddy, MD, MBBS. Now, agents such as duvelisib (Copiktra) are generating excitement in the relapsed/refractory setting.

In the phase 3 ECHELON-2 trial (NCT01777152), brentuximab vedotin plus CHP was compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with CD30-positive PTCL. Results showed that the brentuximab combination reduced the risk of death by 34% (HR, 0.66; 95% CI, 0.46-0.95; P =.024) versus CHOP; moreover, the combination led to a 29% reduction in the risk of disease progression or death (HR, 0.71; 95% CI, 0.54-0.93; P =.011).1 These data led to the November 2018 FDA approval of brentuximab vedotinfor use in combination with chemotherapy in the frontline treatment of patients with CD30-positive PTCL.

“This is quite a significant improvement that we have seen in PFS compared with the standard treatment of CHOP. The key finding here is that in patients with CD30-positive [disease], the treatment of choice would be the addition of brentuximab vedotin,” said Reddy. “However, most of the patients on this study had anaplastic large cell lymphoma, which does express CD30. We are still dealing with a group of patients who are CD30 negative and that's quite a significant population that includes PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and other mature T-cell lymphomas; these do not express CD30.”

In the relapsed/refractory setting, duvelisib has shown promise in the phase 2 PRIMO trial (NCT03372057), where it was evaluated at 2 doses: 25 mg twice daily and 75 mg twice daily. Results presented during the 2019 ASH Annual Meeting showed that the overall response rate (ORR) per investigator assessment was 35% and 54% at the respective doses.2 When evaluated by a blinded independent review committee, the ORRs were 40% and 62%, respectively.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Reddy, an associate professor of medicine at the Vanderbilt University Medical Center, discussed the significance of the ECHELON-2 trial in PTCL, the need for novel therapies for those with CD30-negative disease, and the excitement surrounding duvelisib in the relapsed/refractory setting.

OncLive®: What was the rationale for the ECHELON-2 trial in PTCL? What was the goal of this research?

Reddy: Until more recently, CHOP has been the standard-of-care therapy for mature T-cell lymphoma with advanced-stage disease. Several trials have looked at improving treatment [beyond] CHOP, with the addition of romidepsin or alemtuzumab. Thus far, we haven't seen any positive studies.

The ECHELON-2 study is designed [to see whether] could we improve on CHOP treatment for patients with PTCL. This was a global, double-blind phase 3 study that randomized patients with advanced PTCL and CD30 positivity to receive either brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone (CHP) or standard CHOP.

What were the key findings of this trial? How did the regimen's safety profile compare to the standard of care?

The key findings of this study, which randomized about 450 patients overall was that it did meet the primary end point of PFS. At a median follow-up of 36.2 months, the median PFS was 48.2 months in patients who received brentuximab vedotin and CHP compared with 20.8 months in patients who were given CHOP. The 3-year PFS rate was 57% [in the brentuximab arm] compared with 44% in the CHOP arm. This was 1 of the first studies that actually showed an improvement in overall survival (OS), as well. At a median follow-up of 42.1 months, the death rate reported in the brentuximab vedotin/CHP group was 23% compared with 32% in the CHOP group; the hazard ratio was 0.66.

What did the safety profile look like? How is granulocyte colony stimulating factor (G-CSF) being utilized in patients who receive this chemotherapy combination?

The major toxicities [observed with the combination] were as expected; they included peripheral neuropathy, neutropenia, nausea, and vomiting. Peripheral neuropathy was present in about 52% of patients; most of these cases were grade 1 or 2. About half of the patients had resolution of their peripheral neuropathy events. The other toxicity to report is that of neutropenia.

Patients on this study did not receive G-CSF. G-CSF prophylaxis was permitted based on investigator discretion. About 49% of patients in the brentuximab vedotin/CHP group experienced grade 3 neutropenia compared with 46% in the CHOP group. It was pretty significant; about half of the patients had neutropenia, which led to febrile neutropenia in about 20% of [patients in] the brentuximab vedotin/CHP group. Per the FDA label, however, G-CSF is recommended as primary prophylaxis for all patients receiving the combination chemotherapy with brentuximab vedotin and CHP.

Are there any next steps for this research?

The question is: What can we do to make things better for that group of patients [who do not have CD30 positivity]? Further research will be focused on [adding] other novel agents and promising drugs to the backbone of brentuximab vedotin/CHP for patients with CD30-positive disease. In patients with CD30 negativity, other combinations with CHOP should be considered.

What is the role of duvelisib in PTCL? How does it fit in with the other options that are available?

At least 4 drugs have been approved for use in the relapsed/refractory setting for PTCL, a couple of [which] are the HDAC inhibitors. Brentuximab vedotin is another agent, along with pralatrexate, which is an anti-folate that is approved treatment for relapsed/refractory disease. A newer agent, duvelisib, is an oral PI3K-γ/δ inhibitor that is currently approved for use in other leukemias and lymphomas. In a phase 1 study that included patients with PTCL and cutaneous T-cell lymphoma [CTCL], the ORR in PTCL was about 50%, which was quite impressive. However, it's a phase 1 study and further investigation is necessary.

Could you speak to the rationale for the PRIMO study with duvelisib?

PRIMO is a multicenter, open-label phase 2 study that is being done in patients with relapsed/refractory PTCL. Here, 120 patients will be randomized to receive duvelisib [at different doses]. Initially, the study was trying to allot 2 cohorts of patients. In cohort 1, duvelisib was dosed at 25 mg twice daily, while in cohort 2, patients were given 75 mg twice daily.

In the initial report that was presented at the 2019 ASH Annual Meeting, the ORR was 35% in 20 patients who received the dose of 25 mg twice daily. In the second cohort of 13 patients who received 75 mg twice daily, the ORR was 54%. Given the significant difference, the investigators decided to have 1 cohort of patients where everyone received a dose of 75 mg twice daily for 2 cycles and pending their response, they had the opportunity to decrease the dose to 25 mg twice a day until disease progression. More data for this trial are pending.

Are any other exciting therapies emerging in this space?

Several other notable drugs are under investigation. Alisertib (MLN8237) is a drug worth mentioning and some newer CD30-targeted agents are also quite exciting. CAR T-cell therapy, of course, [is another notable modality that is generating excitement].

What would you say is your take-home message regarding this research?

The ECHELON-2 study is definitely an interesting [study] and a treatment shift, paradigm change in the field given the fact that there was an improvement in PFS and OS. Note that this is for patients who do express CD30-positivity; while on the study, patients had to express >10% of CD30 positivity, as defined by immunohistochemistry staining. The accrual they have received is for any patients who have CD30 expression of >1%, the combination therapy could be used. First, in all our patients who have T-cell lymphomas, it is imperative that we check the CD30 status before we make any treatment decisions.

References

1. Horwitz S, O'Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240. doi:10.1016/S0140-6736(18)32984-2.

2. Verastem Oncology presents phase 2 PRIMO study data evaluating duvelisib in relapsed or refractory peripheral T-cell lymphoma at the American Society of Hematology 2019 Annual Meeting. News release. Verastem, Inc. December 7, 2019. Accessed November 15, 2020. https://bit.ly/36EThUv.