Remaining ECHELON-2 Questions Spark Novel Research Efforts in PTCL

Jakub Svoboda, MD

Questions from the phase 3 ECHELON-2 trial (NCT01777152), which led to the 2018 FDA approval of brentuximab vedotin (Adcetris) plus chemotherapy for patients with CD30-expressing peripheral T-cell lymphoma (PTCL), have given way to additional research efforts with the hope of tailoring clinical trials to specific T-cell lymphoma subtypes, explained Jakub Svoboda, MD.

“PTCL is a challenging disease [to treat] on many levels,” said Svoboda. “It is challenging for the patients because, unfortunately, the outcomes remain worse compared with B-cell non-Hodgkin lymphoma, for example. However, ECHELON-2 was an interesting trial, and [the results are] very applicable to our clinical practice when we see patients with [CD30-positive] PTCL.”

During the virtual 2020 American Society of Hematology (ASH) Annual Meeting and Exposition, updated results of the ECHELON-2 trial showed that after 5 years, brentuximab vedotin plus cyclophosphamide, doxorubicin hydrochloride, and prednisone (CHP) continued to provide clinically meaningful benefit compared with CHP plus vincristine (CHOP) in patients with CD30-positive PTCL.

The estimated 5-year progression-free survival (PFS) rate, with a median follow-up of 47.6 months, was 51.4% with brentuximab vedotin plus CHP versus 43.0% with CHOP (HR, 0.70; 95% CI, 0.53-0.91; P = .0077).

Additionally, prespecified analyses revealed that the majority of subgroups, including ALK-positive and ALK-negative systemic anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), angioimmunoblastic T-cell lymphoma (AITL), and PTCL–not otherwise specified (NOS), favored the experimental arm versus the control arm.

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Svoboda, an associate professor of medicine at the Hospital of the University of Pennsylvania and a physician at the Abramson Cancer Center of Penn Medicine, discussed the results of the ECHELON-2 trial and explained where clinical research is headed in PTCL.

OncLive^®: How has the incidence of PTCL affected clinical research?

Svoboda: Patients with PTCL, as a group, have worse outcomes [compared with those who have other types of Hodgkin lymphomas]. For us in clinical research, PTCL is challenging because it is a rare type of lymphoma, which makes it difficult to conduct clinical trials. Around 15% of non-Hodgkin lymphomas in the United States are of T-cell origin. Also, T-cell lymphomas are a very heterogenous group of diseases; it is not just one [type of] T-cell lymphoma. The most common type tends to be PTCL-NOS, but there is also ALCL, AITL, ATLL, [and other subtypes]. So, designing randomized clinical trials that are powered for good statistics presents a challenge.

What was exciting about the ECHELON-2 trial?

One of the really great efforts and [well-designed] trials to move the field forward was the ECHELON-2 trial in PTCL. [Findings from the] trial were presented by [Steven M. Horowitz, MD, of Memorial Sloan Kettering Cancer Center] during the 2018 ASH Annual Meeting & Exposition and later published in Lancet in 2019.

The randomized trial [enrolled] patients with PTCL. Patients had to express CD30. All patients with ALCL express CD30, and approximately 50% of other T-cell lymphomas express CD30. Patients were randomized to CHOP chemotherapy versus brentuximab vedotin plus CHP, which is basically CHOP without vincristine. Vincristine was removed because [it could potentially] worsen neuropathy when given with brentuximab vedotin.

ECHELON-2 included about 450 patients; this was a large trial [that accrued patients] in many countries and at more than 100 sites. Again, this speaks to how difficult it is to do clinical trials in [T-cell lymphoma]. In the breast cancer world, enrolling 450 patients would be considered a small trial. However, ECHELON-2 was a very large trial.

The results of the study showed that the end points were met and that the experimental arm of brentuximab vedotin plus CHP showed benefit [compared with CHOP]. The median PFS was about 48 months in the experimental arm versus about 20 months in the control arm. The overall survival [OS] was statistically improved in the experimental arm [versus the control arm]. As investigators, we are really happy to see improvements in OS. The median OS hasn’t yet been reached in the experimental arm and was about 17.5 months with CHOP.

According to the prespecified subanalyses, [benefit was observed with brentuximab vedotin plus CHP] across all subtypes, although a lot of the benefit [was driven by] the patients with ALCL.

Was neuropathy a prohibitive toxicity with the brentuximab vedotin–based regimen?

We expected to see some neuropathy because of the brentuximab vedotin; however, surprisingly, the neuropathy wasn’t very [substantial] compared with the ECHELON-1 trial [NCT01712490] in Hodgkin lymphoma. That trial used brentuximab vedotin plus AVD [doxorubicin, vinblastine, and dacarbazine] versus ABVD [AVD plus bleomycin]. I think the combination of brentuximab vedotin and vinblastine is what caused a lot of the neuropathy [in ECHELON-1].

[In ECHELON-2], the rates of neuropathy were quite similar in both arms. Overall, the regimen was well tolerated. So, from now on, at least at Penn Medicine, we use brentuximab vedotin plus CHP for patients with CD30-positive PTCL. This definitely feels justified if we look at the statistics [from ECHELON-2]. We saw about a 30% reduction in the risk of progression and a 34% reduction in the risk of death using the [brentuximab vedotin–based regimen].

What questions remain regarding CD30 expression in PTCL?

[In ECHELON-2], the rates of neuropathy were quite similar in both arms. Overall, the regimen was well tolerated. So, from now on, at least at Penn Medicine, we use brentuximab vedotin plus CHP for patients with CD30-positive PTCL. This definitely feels justified if we look at the statistics [from ECHELON-2]. We saw about a 30% reduction in the risk of progression and a 34% reduction in the risk of death using the [brentuximab vedotin–based regimen].

What other questions were left unanswered by the ECHELON-2 trial?

The other big question that should be answered in a large randomized clinical trial is: What is the role of autologous stem cell transplant [ASCT] as a consolidative treatment? In a lot of settings, including the frontline setting, we have already ruled out that ASCT at the end of therapy helps. However, traditionally and based on nonrandomized data, we would get the best results using CHOP plus ASCT at the end of transplant, usually after 6 cycles, in PTCL.

The ECHELON-2 trial didn’t ask the question about whether ASCT should be included, and a minority of patients in ECHELON-2 [underwent] transplant in the end. So, the trial couldn’t really address the question of whether transplant would work. Some other attempts have looked into that. ASCT [seemed to be] effective, but those were very biased data. Patients who got transplant were younger or in different positions compared with patients who did not [undergo transplant]. So, the role of transplant is a big question for us. Should we offer transplant in patients who achieve a complete response with brentuximab vedotin plus CHP, or should we watch them as was done in ECHELON-2?

What developments are coming down the pike to improve upon the results from ECHELON-2?

We at Penn Medicine are very involved in developing cellular therapies. Something that is of interest is working on creating focused CAR T-cell therapies. This presents a lot of challenges because we are trying to use T cells to kill the cancer cells. T cells and B cells are different. If we have an active T cell, we have to be careful that the cells do not kill themselves. A lot of challenges are being addressed in our labs.

The frontline setting [in PTCL] has a lot of room for improvement. With better understanding of the biology and the actions of different small molecules on certain mutations, perhaps we can improve the frontline landscape and tailor therapy to more specific biologies. Right now, clinical trials put all of the T-cell lymphoma subtypes together. However, I think we are getting to a point where we have to individualize [clinical trials]. So, trials are being planned that will open very soon. For example, an Alliance trial is [opening] that is using CHOP as a backbone with other smaller molecules, such as duvelisib [Copiktra]. Hopefully, this approach will improve frontline outcomes in this very challenging- to-treat disease.

Reference

1. Horwitz SM, O’Connor OA, Pro B, et al. The ECHELON-2 trial: 5-year results of a randomized, double-blind, phase 3 study of brentuximab vedotin and CHP (A+CHP) versus CHOP in frontline treatment of patients with CD30-positive peripheral T-cell lymphoma. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 1150. Accessed January 15, 2021. https://ash.confex.com/ash/2020/webprogram/Paper134398.html