FDA Approves Brentuximab Vedotin for Frontline CD30+ PTCL

The FDA has approved brentuximab vedotin (Adcetris) for use in combination with chemotherapy for the frontline treatment of patients with CD30-expressing peripheral T-cell lymphoma (PTCL).

The approval, which follows a breakthrough therapy designation, is based on the phase III ECHELON-2 trial, in which combining frontline brentuximab vedotin with CHP (cyclophosphamide, doxorubicin, prednisone) 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% (0.71; 95% CI, 0.54-0.93; P = .011) compared with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).¹

Key secondary endpoints also demonstrated superiority with the brentuximab vedotin combination, including objective response rate (83% vs 72%; P = .003), complete remission rate (CR; 68% vs 56%; P = .007), and progression-free survival (PFS) in patients with systemic anaplastic large cell lymphoma (sALCL; HR = 0.59; 95% CI, 0.42-0.84; P = .003).

“The current standard of care for initial treatment of peripheral T-cell lymphoma is multi-agent chemotherapy. That treatment has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments,” Steven Horwitz, MD, Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, said in a statement.

“The ECHELON-2 clinical trial demonstrated Adcetris plus CHP was superior to the current standard of care, CHOP, for both progression-free survival and all other key secondary endpoints, including, most importantly, overall survival. With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” added Horwitz.

In a statement, the FDA noted that a new review program had acclerated the pace of the approval, which occurred less than 2 weeks from the date that the complete application was submitted.

“The Real-Time Oncology Review (RTOR) program allows the FDA to access key data prior to the official submission of the application allowing the review team to begin their review earlier and communicate with the sponsor prior to the application’s actual submission,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products, said in a statement.

“When the sponsor submits the completed application, the review team will already be familiar with the data and be able to conduct a more efficient, timely and thorough review. RTOR allowed the FDA to approve this indication within two weeks of the completed application’s submission,” added Pazdur.

The double-blind, multicenter, placebo-controlled phase III ECHELON-2 trial randomized approximately 450 newly diagnosed patients with CD30-expressing PTCL, also known as mature T-cell lymphoma, to brentuximab vedotin plus CHP or standard CHOP. PFS per independent review was the primary endpoint, with secondary endpoints including overall survival, PFS in patients with sALCL; approximately 75% of the overall population), objective response rate, CR rate, and safety.

According to Seattle Genetics, adverse events (AEs) across all grades reported in ≥20% of patients receiving the brentuximab vedotin combination were peripheral neuropathy, nausea, diarrhea, neutropenia, lymphopenia, fatigue, mucositis, constipation, alopecia, pyrexia, vomiting, and anemia. Serious AEs occurring in ≥2% of patients in the brentuximab vedotin arm were febrile neutropenia, pneumonia, pyrexia, and sepsis. Based on the study results, the investigators recommend that patients with PTCL being treated with frontline brentuximab vedotin plus CHP should receive G-CSF beginning at cycle 1.

In March 2018, the FDA approved brentuximab vedotin for use in combination with chemotherapy as a frontline treatment for adult patients with stage III or IV classical Hodgkin lymphoma based on findings from the phase III ECHELON-1 trial, which demonstrated superior PFS with brentuximab vedotin plus Adriamycin, vinblastine, and dacarbazine (AVD) compared with standard ABVD (AVD plus bleomycin).

In the study, the brentuximab vedotin regimen reduced the risk of progression, death, or initiation of new therapy by 23% compared with ABVD. The 2-year modified PFS rate was 82.1% with brentuximab vedotin compared with 77.25% for standard chemotherapy (HR, 0.77; 95% CI, 0.60-0.98; P = .035).²

The phase III ECHELON-1 trial enrolled 1334 patients with stage III/IV classical Hodgkin lymphoma. All patients had not received prior treatment with systemic chemotherapy or radiotherapy and had an ECOG performance status of ≤2. Patients ranged in age from 18 to 83, the median age was 36 years, and 58% were men.

In both arms, treatment was given on days 1 and 15 of a 28-day cycle. Doxorubicin was given at 25 mg/m², vinblastine was administered at 6 mg/m², and patients received dacarbazine at 375 mg/m². In the investigational arm, brentuximab vedotin was administered at 1.2 mg/kg and in the control group bleomycin was administered at 10 units/m².

The primary endpoint of the study was modified PFS by independent review committee. Under the modified criteria, PFS was defined as time to progression, death, or receipt of additional therapy for those not in CR. The modified endpoint was meant to eliminate the potential impact of consolidation treatment with chemotherapy or radiotherapy. Secondary endpoints included overall survival and safety.

PFS was met with 117 events in the brentuximab vedotin arm and 146 events in the AVBD arm. At a median follow-up of 24.9 months, the 2-year modified PFS was 82.1% (95% CI, 78.7-85.0) with the brentuximab vedotin regimen compared with 77.2% (95% CI, 73.7-80.4) with ABVD.

The CR rate was 73% for the brentuximab vedotin arm and 70% for the ABVD arm. In addition, researchers found that 33% fewer patients treated with the brentuximab vedotin regimen received subsequent chemotherapy or high-dose chemotherapy and transplant compared with the patients treated with ABVD.

Brentuximab vedotin also has approved indications for patients with classical Hodgkin lymphoma at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation; classical Hodgkin lymphoma after failure of auto-HSCT or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates; sALCL after failure of at least one prior multiagent chemotherapy regimen; and primary cutaneous anaplastic large cell lymphoma or CD30-expressing mycosis fungoides in patients who have received prior systemic therapy.

References

1. FDA Grants Breakthrough Therapy Designation to ADCETRIS® (Brentuximab Vedotin) for Frontline Peripheral T-Cell Lymphomas. Published online November 15, 2018. Accessed November 15, 2018. https://bit.ly/2zeyd7p.
2. Connors J, Jurczak W, Straus D J., et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 echelon-1 study. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 6.

No new safety signals emerged with brentuximab vedotin. The label for the antibody-drug conjugate does include a Boxed Warning regarding the risk of progressive multifocal leukoencephalopathy. Seattle Genetics and Takeda Pharmaceutical, the co-developers of brentuximab vedotin, will be presenting additional ECHELON-2 findings at the 2018 ASH Annual Meeting.