Targeted Agents Lead Treatment Advances in T-Cell Lymphoma

Jasmine M. Zain, MD

Results from the phase III ECHELON-2 trial set a precedent for targeted therapy in T-cell lymphoma by showing the benefit of adding brentuximab vedotin (Adcetris) to standard chemotherapy in patients with advanced CD30-expressing peripheral T-cell lymphoma (PTCL), said Jasmine M. Zain, MD.

In the trial, 452 patients with newly diagnosed CD30-positive (≥10% of neoplastic cells by local review) PTCL were randomized to receive brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP; A+CHP) or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Results showed that A+CHP reduced the risk of death by 34% (HR, 0.66; 95% CI, 0.46-0.95; P = .024) and the risk of disease progression or death by 29% (HR, 0.71; 95% CI, 0.54-0.93; P = .011) compared with CHOP. These results served as the basis for the regimen’s approval in November 2018 as frontline therapy for patients with CD30-expressing PTCL.

“If you see a patient with newly diagnosed PTCL, it is important to ask the pathologist to check for CD30,” said Zain. “It's not routinely done, so if you don't see it on your pathology report, ask for it, because it may change the patient’s course of treatment.”

In addition to CD30-targeted treatments, investigators are evaluating other novel targets such as CCR4 and CD25, by way of antibody-drug conjugates (ADCs) and bispecific T-cell engagers (BiTEs).

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Zain, hematologist/oncologist, associate clinical professor, Hematology and Hematopoietic Cell Transplantation, and director, T cell Lymphoma program, Toni Stephenson Lymphoma Center, City of Hope, discussed the phase III ECHELON-2 trial and the ongoing work being done in PTCL and other T-cell lymphomas.

OncLive^®: What has generated the most excitement in the field of T-cell lymphoma?

Zain: [There was] a very exciting trial in T-cell lymphomas called ECHELON-2; it's exciting because it's the first prospective, randomized trial that has shown an improvement in survival in patients with PTCL. The trial has resulted in the adoption of A+CHP as the standard of care for the frontline treatment of patients with CD30-expressing PTCL; this has been incorporated into the National Comprehensive Cancer Network (NCCN) guidelines.

Could you elaborate on the key aspects of the trial?

It was an international, multicenter, prospective trial that was conducted over 3 years. T-cell lymphoma is a rare lymphoma, so it is hard to conduct these large trials in a single center. It was a double-blinded trial, so investigators did not know which arm each patient was going to be on. Patients had to have CD30 expression in their tumor biopsies; at least 10% of the tumor had to express CD30 to be considered CD30-positive. Subsequently, patients were randomized to receive either CHOP or A+CHP. There were about 250 patients in each arm and they received 6 to 8 cycles of treatment.

At the last data cut-off in October 2018, we saw higher response rates, complete responses, and improved progression-free survival and overall survival in the A+CHP arm. All of the endpoints of the trial favored A+CHP.

In terms of toxicity, infections were an issue. There were some infection-related events. After primary prophylaxis with granulocyte colony-stimulating factor was instituted in the A+CHP arm, the toxicities were balanced in both arms. Neuropathy was a big concern because brentuximab vedotin is known for this adverse event (AE). However, overall, neuropathy was pretty similar between the arms. The AEs were acceptable. [This combination] is definitely an option for patients in this setting.

What are the next steps for this research?

CD30 expression is not standardized in labs, so that needs to be evaluated further. The FDA approved this combination for the frontline treatment of patients with PTCL. They’re only requiring patients to have CD30 expression of ≥1%, but we know CD30 expression is variable. We have to make it more uniform. Secondly, patients in the trial received 6 to 8 cycles of chemotherapy. The trial was not designed to look at maintenance strategy; in PTCL, this may consist of a stem cell transplant. Once patients achieve remission, they usually undergo a stem cell transplant; that's still controversial. We were hoping to get an answer in this trial, but it was not designed to look at that question.

The next big question we’ll have to answer is whether patients who achieve a remission need a transplant, or whether they can get away with some other kind of maintenance regimen. Additionally, what about the patients who are CD30-negative? We still don't have good treatments for them, or at least comparable treatments. There's still a lot of research that needs to be done.

Could you expand on what is known about CD30 and its role in T-cell lymphomas?

CD30 is a molecule that's expressed on activated lymphocytes—both B and T lymphocytes. It’s not unique to cancers, but it is expressed on many different types of lymphomas. In T-cell lymphomas, CD30 is uniformly expressed in anaplastic large cell lymphoma (ALCL), which is one of the first diseases for which this drug was initially approved. Brentuximab vedotin was approved for use in relapsed/refractory ALCL after patients failed previous therapy. CD30 is also expressed in PTCL, but not uniformly and with variable expression. We know from various studies in PTCL that the degree of expression does not seem to correlate with response. With better diagnostic categories we may be able to find a better way to [evaluate CD30 expression] and show a correlation with response.

Could you discuss other ongoing trials that are generating excitement in PTCL and other lymphomas?

There are multiple trials in several disease categories. We know from our experience with chemotherapy that [this treatment is] not really the answer to PTCL. As such, researchers are looking into immunotherapies. CAR T-cell therapy hasn't really panned out [in this space], but there is a lot of ongoing research being done with BiTEs. We’re also looking into other targets for ADCs. We just completed a trial with a CD25-targeted ADC; those targets can also be used for BiTEs.

Mogamulizumab-kpkc (Poteligeo) is another exciting drug which was approved in 2018 for the treatment of patients with [mycosis fungoides and Sézary syndrome, which are 2 subtypes of] cutaneous T-cell lymphoma (CTCL). The agent targets CCR4, which is another marker of T-cell lymphomas; it is highly expressed in a disease called adult T-cell leukemia/lymphoma, which is a subtype of T-cell lymphoma and CTCL. Certainly, there are several ongoing trials exploring this agent in combination with other drugs to try to improve response rates. There are many exciting things happening in the world of PTCL.

Are there any other targets under investigation?

Right now, researchers are moving towards molecular signatures and molecular expression with different types of gene chips to figure out if there are specific pathways that can be targeted. One of the targets that is appearing is the epigenetic pathway. We know that the HDAC inhibitors work for some T-cell lymphomas. Romidepsin (Istodax), vorinostat (Zolinza), and belinostat (Beleodaq) induce response rates of about 30% in PTCL in the relapsed setting.

Some of these T-cell lymphomas have TET2 and RHOA mutations, which can be targeted with hypomethylating agents. Combination strategies for epigenetic targeting is certainly something that's being explored. We have a trial at City of Hope with lenalidomide (Revlimid) and romidepsin in the upfront setting for older patients who are not eligible for chemotherapy. The responses [seen thus far] are pretty exciting.

What key challenges remain in this space?

These diseases are rare and they are difficult to diagnose. There are many different subtypes, so it is very hard to do clinical trials that focus on one specific subtype. Usually, you have to collaborate and do multicenter trials. That's one of the reasons why the ECHELON-2 trial could be conducted—so many centers and people were involved. Improving our understanding of the pathogenesis and using that as a base to develop treatments would be the best approach. Thus far, using general chemotherapy or borrowing from other diseases has really not helped too much.

What is your take-home message to community oncologists?

The NCCN guidelines have changed for frontline treatment of patients with CD30-expressing PTCL. In the relapsed setting, always look for CD30 expression; it can be variable. The second thing to remember is to look for clinical trials, because we don't really have good standard treatments. Clinical trials are promising, and we're hoping that they we will help us improve overall outcomes. However, this will only work if patients are referred to us for trials. Our job is to make sure the trials are well designed and ask the appropriate questions.

Horwitz SM, O’Connor OA, Pro B, et al. The ECHELON-2 trial: results of a randomized, double-blind, active-controlled phase 3 study of brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline treatment of patients with CD30+ peripheral T-cell lymphomas. Blood. 2018;132(suppl 1):997. doi: 10.1182/blood-2018-99-110563.