Brentuximab Vedotin Combos Among Key Advances in Hodgkin, T-Cell Lymphoma

Alison J. Moskowitz, MD

Following separate indications of brentuximab vedotin (Adcetris) for the treatment of patients with Hodgkin and T-cell lymphoma, investigators are continuing to dissect the role of the antibody-drug conjugate within each of these paradigms, said Alison J. Moskowitz, MD.

In March 2018, the FDA approved brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the first-line treatment of patients with stage III/IV classical Hodgkin lymphoma, based on an improvement in progression-free survival (PFS) with the regimen compared with AVD plus bleomycin (ABVD) in the phase III ECHELON-1 trial.¹

A 3-year update of the trial showed a modest PFS benefit with the combination of brentuximab vedotin to AVD compared with ABVD for the above-mentioned patient population. The median PFS at 3 years was 83.1% versus 76.0%, respectively.²

"The difference continues to be fairly small between the 2 groups,” expressed Moskowitz. “Brentuximab vedotin plus AVD is associated with increased toxicity, so even though there is a small PFS benefit, it's not necessarily the right treatment for everybody."

The data were stronger for brentuximab vedotin in patients with previously untreated CD30-positive peripheral T-cell lymphoma (PTCL), for which the FDA approved the agent in November 2018. The approval was based on results from the ECHELON-2 study, which showed that the median PFS was 48.2 months with brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) compared with 20.8 months for CHP plus vincristine (CHOP; HR, 0.71; 95% CI, 0.54-0.93; P = .011).³

“In T-cell lymphoma, the ECHELON-2 study has changed the standard of care for patients who have anaplastic large cell lymphoma (ALCL), as well as those with CD30-positive T-cell lymphoma. Brentuximab vedotin is the frontline treatment, though we still consider upfront autologous stem cell transplant (ASCT) for patients who are eligible before,” Moskowitz added.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Moskowitz, clinical director of the Lymphoma Inpatient Unit at Memorial Sloan Kettering Cancer Center, discussed pivotal data for brentuximab vedotin in Hodgkin and T-Cell Lymphoma, as well as other ongoing developments in these paradigms.

OncLive^®: How have treatment strategies changed for patients with advanced Hodgkin lymphoma?

Moskowitz: We know that the interim PET scans, which are PET scans after 2 cycles of chemotherapy, can predict how a patient is going to perform. Multiple studies have looked at modifying treatment based on interim PET results, which could indicate a need to reduce or escalate treatment.

The other major impact in the relapsed/refractory setting of Hodgkin lymphoma is the availability of novel drugs, including brentuximab vedotin, and the checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda). Now, those drugs are starting to be evaluated earlier in treatment.

What is the impact of the 3-year results of the ECHELON-1 trial in Hodgkin lymphoma?

Based on that update, we know the PFS remained superior for patients who received brentuximab vedotin plus AVD compared with patients who received standard AVBD.

There are certain patients who I would tend not to give [the brentuximab vedotin] regimen to. There was a subset of patients from this study [with interesting results]; patients over the age of 60 years did not benefit from brentuximab vedotin plus AVD, which was probably due to increased toxicity. Also, more favorable-risk patients did not appear to derive as much benefit from this regimen.

However, high-risk patients who cannot receive bleomycin may be better candidates for brentuximab vedotin plus AVD.

What can we expect to see with immunotherapy in this space? What challenges remain?

Although the majority of patients will respond to immunotherapy, a very small number will obtain a complete response. We are still trying to figure out the mechanism of response and how to determine the best candidates for treatment who can achieve a CR.

In the relapsed/refractory setting, we don’t know how long patients should stay on treatment and when treatment should be stopped.

There is certainly interest in evaluating these drugs in the first- or second-line setting, as well as determining whether immunotherapy is a better treatment than standard chemotherapy. Multiple clinical trials are evaluating these drugs with potentially good correlative studies. Hopefully, we will learn which patients are most likely to benefit early on.

Moving to non-Hodgkin lymphoma, could you discuss the impact of the ECHELON-2 data?

ECHELON-2 was a study for patients with either ALCL—which is always CD30-positive—or patients with CD30-positive T-cell lymphoma, such as PTCL—not otherwise specified or angioimmunoblastic T-cell lymphoma.

Previously untreated patients were randomized to either CHOP for 6 cycles or brentuximab vedotin plus CHP—which was CHOP without vincristine to avoid overlapping toxicity.

Then, patients were either monitored or consolidated by ASCT, which has often been the standard in first remission of T-cell lymphoma.

The ECHELON-2 results showed a significant improvement in both PFS and overall survival for patients who received brentuximab vedotin plus CHP. It was practice-changing for this patient population, and it led to the FDA approval of brentuximab vedotin plus CHP in the frontline setting.

The majority of patients on the study had ALCL, so the results amongst that group drove the overall results. Though patients who had the other types of T-cell lymphoma were included as long as they had CD30-positive disease, their improvement was not significant. They were a very small subset, so it's hard to interpret their benefit.

How is the role of chemotherapy changing with the introduction of these novel agents?

Hodgkin lymphoma is still highly curable with chemotherapy. Certainly, we are using the novel agents and immunotherapy regularly in the relapsed/refractory setting, but that is for patients who [already received standard chemotherapy]. It is difficult to change the frontline treatment of Hodgkin lymphoma because chemotherapy has worked fairly well.

In T-cell lymphoma, the most effective drug is brentuximab vedotin. Though it is specifically for those with CD30-positive disease, it has clearly made an incredible impact for those patients.

In general, the outcome for patients with T-cell lymphoma is pretty unfavorable. There is a lot of room for improvement in all settings, including in the frontline setting.

As we find new drugs that are active in these diseases, investigating how we can incorporate them in earlier lines of treatment will be interesting.

What is your take-home message to colleagues who are working in this space?

Generally, my approach for stage III/IV Hodgkin lymphoma is per the RATHL study. Patients received 2 cycles of ABVD, and then their PET scan after 2 cycles dictated whether we should drop bleomycin for the next 4 cycles, or escalate treatment to something stronger, such as escalated BEACOPP.

At this time, a small subset of patients [with Hodgkin lymphoma] may benefit from treatment as per the ECHELON-1 trial, including patients who have a high-risk international prognostic score, as well as those who cannot tolerate bleomycin.

[CD30-negative] T-cell lymphoma is an active area of research with some exciting studies on the horizon, but we still have a lot of work to do.

References

1. Connors J, Jurczak W, Straus D J., et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344. doi: 10.1056/NEJMoa1708984.
2. Straus DJ, Dlugosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma: three-year update of the ECHELON-1 study. J Clin Oncol. 2019;37(suppl; abstr 7532). doi: 10.1200/JCO.2019.37.15_suppl.7532.
3. 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, randomized phase 3 trial. Lancet. 2018;393(10168):229-240. doi: doi.org/10.1016/S0140-6736(18)32984-2.