Expert offers insight into treatment of CD30-expressing lymphomas
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Since the discovery of the CD30 molecule in 1982, progress has been made in the treatment and survival outcomes for patients with CD30-positive disease. Nearly 30 years after this discovery, brentuximab vedotin (Adcetris, Seattle Genetics), an antibody targeting CD30, was approved by the FDA.
“The initial indication for brentuximab vedotin was for use in relapsed and refractory CD30-expressing lymphomas, such as Hodgkin lymphoma and anaplastic T-cell lymphoma, because it showed significant response rates in these difficult-to-treat populations,” Anne W. Beaven, MD, director of the lymphoma program and associate professor in the division of hematology/oncology at the University of North Carolina Lineberger Comprehensive Cancer Center and UNC School of Medicine, said during an interview with Healio. “Since that time, its approved uses have expanded to include the front-line setting as well as consolidation. This therapy that can directly target CD30-positive lymphomas transcended treatment for these patients.”
Healio spoke with Beaven about the discovery of CD30 in lymphoma and available agents that target CD30 as well as other treatments on the horizon.
How common is CD30 in lymphoma and in what subtypes is it most prevalent?
There are two lymphomas that universally express CD30. The first is Hodgkin lymphoma, which is the most frequent lymphoma seen in children, but also occurs in adults, and is a highly curable lymphoma with front-line therapy. However, if the patient relapses, the prognosis is significantly worse, although the outlook has improved during the past 10 years with the approval of new agents, such as brentuximab vedotin, and checkpoint inhibitors, such as nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck).
In clinical trials of brentuximab vedotin in relapsed Hodgkin lymphoma, high response rates were seen in heavily pretreated patients. Responses were durable in some patients who achieved a complete response with brentuximab vedotin.
It is also FDA-approved as part of front-line therapy for patients with advanced-stage disease. As consolidation after stem cell transplant in patients who are at high-risk for relapse, clinical trial results showed a 2-year, PFS of 63% with brentuximab vedotin maintenance vs. 51% without.
Within the non-Hodgkin lymphoma group, the T-cell lymphoma anaplastic large cell lymphoma universally expresses CD30. While anaplastic T-cell lymphoma has a better prognosis than many other T-cell lymphomas, it is more difficult to cure than Hodgkin lymphoma, especially if it relapses.
For T-cell lymphoma, brentuximab vedotin was initially FDA-approved for relapsed or refractory disease based on a complete remission of about 67% compared with 15% in most other agents that were approved for this indication. Brentuximab vedotin is now part of front-line therapy for many patients with CD30-positive T-cell lymphoma in combination with a CHOP regimen. In addition to the above, CD30 is variably expressed in other peripheral T-cell and cutaneous T-cell lymphomas and the occasional diffuse large B-cell lymphoma.
Are there other agents that target CD30 in the pipeline, or new approaches to targeting CD30?
The new approach that I am most excited about is the research we are conducting here at UNC Lineberger Comprehensive Cancer Center. This research investigates the use of CAR T-targeting CD30 in patients with relapsed or refractory CD30-positive lymphoma, including Hodgkin lymphoma, T-cell lymphomas and cutaneous T-cell lymphomas. We presented preliminary data from trials evaluating CAR-T therapy for patients with the CD30-positive lymphoma at the American Society of Hematology Annual Meeting in 2018. The preliminary results were exciting for a group of patients who were heavily pretreated.
How does the efficacy of anti-CD30 agents compare with anti-PD-1 agents for lymphoma? How does a clinician decide between the two?
The development of both anti-CD30 antibodies and anti-PD-1 inhibitors have been game changers for the treatment of CD30-positive lymphomas. Both have shown high response rates and durable responses in some patients.
At this time, the anti-PD1 inhibitors are not FDA-approved for use in T-cell lymphomas, so outside of a clinical trial, the decision to use brentuximab vedotin versus an anti-PD1 agent is only relevant when treating patients with relapsed or refractory Hodgkin lymphoma.
If a patient received brentuximab vedotin as part of front-line therapy, then a clinician is likely to try a PD-1 inhibitor for relapsed or refractory disease. If the patient has never received either of these therapies, then the clinician must also assess the toxicities associated with each drug to make the best decision. Peripheral neuropathy is a frequent side effect of brentuximab vedotin, so it needs to be avoided in any patient with an underlying neuropathy. The anti-PD1 inhibitors work by augmenting the immune response to the cancer, which can also cause the immune system to target the normal parts of the patient, such as the lungs or gastrointestinal tract. Therefore, these agents need to be avoided in patients who already have a known autoimmune disease.
Ultimately, many patients will eventually get both drugs for the treatment of their lymphoma, and there are no data at this time telling us that one drug should be tried before moving on to the other drug. Further, much of the active research at this time is investigating using brentuximab vedotin in combination with anti-PD1 agents. Preliminary results are very encouraging, so it may be that this is the approach taken with many patients in the future.
Along with CD30, what are some other molecules often targeted for the treatment of rare lymphomas, like T-cell lymphomas?
Mogamulizumab is an antibody that targets CCR4 and is FDA-approved for use in relapsed or refractory cutaneous T-cell lymphoma. However, there are not many other T-cell lymphoma targets that are widely appealing for clinical development partly due to concerns about toxicity. One of the reasons that drugs targeting CD30 have been so effective and safe is because this target is expressed on malignant cells but not on normal T-cells. Normal circulating T-cells are part of the immune system, so agents that are targeted toward markers found on normal cells and lymphoma cells could result in significant suppression of the immune system and lead to infectious complications.
Are there any downsides or issues that need to be resolved regarding the use of anti-CD30 agents?
For both the PD-1 inhibitors and brentuximab vedotin, the big issue is when to stop treatment. This is an increasing problem with a lot of novel oncology drugs. With these agents that are quite well-tolerated, most of the clinical trials allow for treatment to continue until serious adverse events or disease progression occur. What we need to figure out is whether we eventually stop the drug in patients who achieve a complete response to therapy vs. committing patients to indefinite therapy.
What options remain if a patient does not respond to anti-CD30 treatment?
This depends. In patients with Hodgkin lymphoma, if they have not already received a PD-1 inhibitor, then this would usually be my go-to drug. If they have already received both drugs, then I would enroll them in a clinical trial of newer agents. There are other single agents that we may use for these patients as well. For the patient with T-cell lymphoma, there are several agents available for relapsed disease, such as romidepsin, pralatrexate (Folotyn, Allos Therapeutics Inc.) or belinostat (Beleodaq, Spectrum Pharmaceuticals).
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