Brentuximab Vedotin Shows Broadening Benefit Across Lymphoma Subtypes

The emergence of the antibody-drug conjugate (ADC) brentuximab vedotin (Adcetris) has had a positive impact on improving overall survival (OS) and progression-free survival (PFS) for patients with T-cell lymphomas and classical Hodgkin lymphoma (cHL), according to Aarthi Shenoy, MD.

“If we examine T-cell lymphomas, we mostly see suboptimal survival,” said Shenoy, in a presentation during the 2020 Institutional Perspectives in Cancer webinar on Hematologic Malignancies. “Most [patients with] T-cell lymphomas have a survival of less than 1 year. [However], if you look at all T-cell lymphomas, about 30% of them will be CD30 positive. That is excluding anaplastic large cell lymphomas (ALCLs), which are always CD30 positive. For [these patients], brentuximab vedotin has become a very useful agent.” 

In the presentation, Shenoy, program director of the Hematology and Oncology Fellowship and an attending hematologist at MedStar Washington Hospital Center, highlighted some of the most prominent data that have emerged with brentuximab vedotin-based regimens in the field of lymphoma.

ECHELON-2 Brings Brentuximab Vedotin to the Forefront of Treatment in PTCL

In the phase 3 ECHELON-2 trial, patients with CD30-positive peripheral T-cell lymphoma (PTCL) were randomized to receive brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, and prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in the frontline setting.¹

Eligible patients had to have at least 10% CD30 expression and no history of grade 2 or greater neuropathy. Patients with ALCL, PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma were included. As required by the European Medicines Agency, 70% of patients had ALCL.

Both arms enrolled 226 patients. In the experimental arm, patients received 1.8 mg/kg of brentuximab vedotin plus 6 to 8 cycles of CHP every 3 weeks. In the chemotherapy-alone arm, patients received 6 to 8 weeks of CHOP every 3 weeks. Additionally, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was recommended.

Findings from the trial demonstrated a 29% reduction in the risk of disease progression or death with the addition of brentuximab vedotin to chemotherapy compared with chemotherapy alone (HR, 0.71; 95% CI, 0.54-0.93; P = .011). Moreover, at 4 years, the median PFS was 48.2 months with brentuximab vedotin plus CHP versus 20.8 months with CHOP.

OS was also improved with the combination. The addition of brentuximab vedotin to chemotherapy reduced the risk of death by 34% compared with CHOP alone (HR, 0.66; 95% CI, 0.46-0.95; P = .0244).

Additionally, brentuximab vedotin plus CHP induced a complete response (CR) rate of 68% compared with 56% with CHOP (P = .007).

Regarding safety, common adverse effects (AEs) included nausea, peripheral sensory neuropathy, neutropenia, diarrhea, constipation, alopecia, pyrexia, vomiting, fatigue, and anemia. The rates of AEs, as well as the rates of treatment discontinuation and death due to AEs were similar between arms. However, patients who received brentuximab vedotin plus CHP experienced higher rates of grade 3 or higher diarrhea versus CHOP, at 6% versus 1%, respectively.

ECHELON-1 Demonstrates Similar Utility With Brentuximab Vedotin in cHL

In the cHL space, the phase 3 ECHELON-1 trial evaluated brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) compared with ABVD (AVD plus vincristine).

The trial enrolled patients with stage III or IV cHL and randomized them 1:1 to receive either 1.2 mg/kg of brentuximab vedotin plus 6 cycles of AVD on days 1 and 15 of each 28-day cycle (n = 664) or 6 cycles of ABVD on the same schedule (n = 670). As in ECHELON-2, primary prophylaxis with G-CSF was recommended. Additionally, PET imaging was performed after cycle 2 of treatment, and patients who had a Deauville score of 5 were then given investigator’s choice of treatment.

At 4 years, brentuximab vedotin plus AVD induced a 31% reduction in the risk of disease progression or death compared with ABVD.²

Moreover, at a median follow-up of 48.4 months, the PFS rates were 81.7% with brentuximab vedotin plus AVD (95% CI, 78.3%-84.6%) versus 75.1% with ABVD (95% CI, 71.4%-78.4%).

Notably, 30% fewer patients who received brentuximab vedotin plus AVD required additional therapy compared with patients who received ABVD.

Regarding safety, the rates of febrile neutropenia were 19% and 8% in the brentuximab vedotin plus AVD and ABVD arms, respectively. The rates of neutropenia were high in both arms, at 91% versus 89%, respectively. Peripheral neuropathy was observed in 67% versus 41% of patients, respectively, but resolved in 62% versus 73% of patients, respectively. Finally, pulmonary toxicities occurred in 2% of patients who were treated with brentuximab vedotin plus AVD versus 7% of patients treated with ABVD.

Novel Brentuximab Vedotin-Based Combos Emerge in Relapsed/Refractory cHL

Despite the survival benefit that has been observed with brentuximab vedotin in the up-front setting, 30% of patients with advanced-stage Hodgkin lymphoma will relapse on or become refractory to therapy, said Shenoy.

As such, the utility of the ADC has been explored for patients who develop relapsed/refractory disease. 

In a phase 1/2 study, brentuximab vedotin plus bendamustine showed remarkable 3-year OS and PFS rates as first salvage therapy in patients with relapsed/refractory Hodgkin lymphoma, according to Shenoy.³ At a median follow-up of 44 months, the OS rate was 92% with this approach (95% CI, 80%-96.9%). At a median follow-up of 38.7 months, the PFS rates were 60.3% in the overall patient population (95% CI, 43.5%-73.6%) and 67.1% in patients who went on to receive autologous stem cell transplant (ASCT) after brentuximab vedotin/bendamustine (95% CI, 47.9%-80.5%).

Findings from another phase 1/2 study showed that brentuximab plus nivolumab (Opdivo) elicited a 98% OS rate at a median follow-up of 22 months in patients with relapsed/refractory cHL.⁴ At 2 years, the PFS rates were 91% for patients who went on to receive ASCT after brentuximab vedotin plus nivolumab and 78% in all treated patients.

“Immunotherapy is now showing therapeutic benefit in the relapsed/refractory setting and may actually surpass what we can do with chemotherapy alone,” said Shenoy.

Brentuximab Vedotin Goes Up Against Pembrolizumab in First-Line cHL

The randomized phase 3 KEYNOTE-204 trial demonstrated superior PFS with pembrolizumab (Keytruda) versus brentuximab vedotin in patients with relapsed/refractory cHL.

Eligible patients had to have relapsed/refractory cHL and be post ASCT or ineligible for ASCT. Patients could have received prior treatment with brentuximab vedotin.

In the trial, patients were randomized 1:1 to receive either 1.8 mg/kg of brentuximab vedotin (n = 152) or 200 mg of intravenous pembrolizumab (n = 148). Both regimens were given every 3 weeks.

Pembrolizumab induced a median PFS of 13.2 months (95% CI, 10.9-19.4) compared with 8.3 months with brentuximab vedotin (95% CI, 5.7-8.8). This translated to 1-year PFS rates of 53.9% versus 35.6%, respectively.⁵

Subgroup analyses revealed that all patients tended to do better with pembrolizumab at varying degrees but irrespective of prior ASCT, disease status, sex, age, ECOG performance status, geographic region, and prior brentuximab vedotin exposure.

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. Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the Echeleon-1 study. Blood. 2019;134(suppl 1):4026. doi:10.1182/blood-2019-124116
3. LaCasce AS, Bociek RG, Sawas A, et al. Three-year outcomes with brentuximab vedotin plus bendamustine as first salvage therapy in relapsed or refractory Hodgkin lymphoma. BR J Haematol. 2020;189(3):e86-e90. doi:10.1111/bjh.16499
4. Moskowitz AJ, Advani RH, Bartlett NL, et al. Brentuximab vedotin and nivolumab for relapsed or refractory classic Hodgkin lymphoma: long-term follow-up results from the single-arm phase 1/2 study. Blood. 2019;134(suppl 1):238. doi:10.1182/blood-2019-122576
5. Kuruvilla J, Ramchandren R, Santoro A, et al. KEYNOTE-204: randomized, open-label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory class Hodgkin lymphoma (R/R cHL). J Clin Oncol. 2020;38(suppl 15):8005. doi:10.1200/JCO.2020.38.15_suppl.8005