In 5-year update of ECHELON-2 study, frontline treatment of patients with peripheral T-cell lymphoma (PTCL) with brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) continues to provide clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) versus CHOP regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy. The results from this updated analysis are published by Dr Steven Horwitz of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues in the Annals of Oncology.
PTCL is a heterogeneous malignancy that is relatively rare, accounting for approximately 10% of all non-Hodgkin lymphomas in Western populations. The most common subtypes of PTCL are nodal PTCLs: PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma, and systemic anaplastic large cell lymphoma (sALCL); sALCL is subdivided into those that harbour a chromosomal translocation involving the anaplastic lymphoma kinase (ALK) gene. Although ALK-positive sALCL has more favourable prognosis in younger patients, older patients or those with higher International Prognostic Index scores (≥2) can have a prognosis that is similar to ALK-negative sALCL.
The rarity of PTCL, the diversity of histologies, and diagnostic challenges have hampered progress in treatment. Historically, the most common treatment of PTCL has been the CHOP or CHOP-like regimens. However, outcomes using frontline treatment with these regimens are typically poor.
With encouraging results and safety demonstrated from a phase I study, the phase III ECHELON-2 study compared frontline treatment of brentuximab vedotin, an antibody-drug conjugate directed to CD30, plus CHP versus CHOP for patients with sALCL or other CD30-positive PTCL. In the primary analysis with a median follow-up of 36.2 months, the 3-year PFS was 57.1% (95% confidence interval [CI] 49.9% to 63.7%) for brentuximab vedotin plus CHP compared with 44.4% with CHOP (95% CI 37.6% to 50.9%); OS also favoured brentuximab vedotin plus CHP over CHOP, with 3-year OS of 76.8% (95% CI 70.4% to 82.0%) with brentuximab vedotin plus CHP versus 69.1% for CHOP (95% CI 62.3% to 74.9%).
Brentuximab vedotin was approved in combination with CHP in the US, Europe, Canada, and other parts of the world either for treatment of patients with previously untreated sALCL or more broadly for treatment of patients with previously untreated CD30-expressing PTCL and has since become an accepted standard-of-care.
In the latest analysis, the study team presents an exploratory analysis of the ECHELON-2 study at 5 years, including PFS per investigator and OS in the intention-to-treat population, results in prespecified subgroups, response rates with brentuximab vedotin treatment after frontline therapy, and peripheral neuropathy resolution and improvement.
ECHELON-2 is a double-blind, randomised, placebo-controlled, active-comparator phase III study in which 452 patients were randomised (1:1) to either 6 or 8 cycles of brentuximab vedotin plus CHP (226 patients) or CHOP (226 patients). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% (95% CI 42.8% to 59.4%) with brentuximab vedotin plus CHP versus 43.0% (95% CI 35.8% to 50.0%) with CHOP (hazard ratio [HR] 0.70; 95% CI 0.53-0.91), and 5-year OS rates were 70.1% (95% CI 63.3% to 75.9%) with brentuximab vedotin plus CHP versus 61.0% (95% CI 54.0% to 67.3%) with CHOP (HR 0.72; 95% CI 0.53-0.99). Both PFS and OS were generally consistent across key subgroups.
Peripheral neuropathy was resolved or improved in 72% of patients in the brentuximab vedotin plus CHP arm and 78% in the CHOP arm.
Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after brentuximab vedotin plus CHP and 50% with subsequent brentuximab vedotin after CHOP.
The authors concluded that in this 5-year update of the ECHELON-2 study, frontline treatment with brentuximab vedotin plus CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP in patients with PTCL, including ongoing remission in >60% of patients with sALCL at 5 years, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.
Prof. Emmanuel Bachy of the Hematology Department, Hospices Civils de Lyon and Lymphoma Immuno-Biology Team, Université Claude Bernard in Lyon, France and Dr. Gilles Salles of the Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center in New York, NY, US wrote in an accompanied editorial that insightful knowledge is to be learned from this updated follow-up and from exploratory analyses presented in the study.
First, retreatment with brentuximab alone or in combination at relapse appears a valuable option for many patients because the overall response rate was 59% with brentuximab vedotin retreatment after brentuximab vedotin plus CHP at least for patients with sALCLs. A higher response rate was observed with brentuximab vedotin retreatment compared with a first use of brentuximab vedotin in relapse/refractory settings, possibly because only responders in first-line were retreated with brentuximab vedotin at relapse. Second, polyneuropathy, which is a known concern during and following brentuximab vedotin therapy, does not appear to be more severe or frequent than following vincristine use in CHOP. Third, no excess in second primary malignancies is reported.
Yet, many questions remain unanswered. The study confirms the absence of a direct predictive link between CD30 expression level and response to brentuximab vedotin-based treatment. Regarding consolidation strategy with stem cell transplant, the lack of evidence-based data is reflected by the fact that about only one-third of patients in complete remission after induction proceeded to stem cell transplant. The benefit of etoposide, especially in young patients with ALK-positive sALCLs, was not addressed in the ECHELON-2 study. Finally, the benefit of adding brentuximab vedotin to a CHOP-based induction in non-sALCLs is still highly hypothetical.
This work was supported by Seagen Inc. and Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited and in part through the US National Institutes of Health / National Cancer Institute grant.
References
- Horwitz S, O’Connor OA, Pro B, et al. The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Annals of Oncology 2022;33(3):288-298.
- Bachy E, Salles G. The upper ECHELON against T-cell lymphoma. Annals of Oncology 2022;33(3):239-241.