Updated and additional analysis of the ECHELON-1 and ECHELON-2 phase III frontline clinical trials of brentuximab vedotin (Adcetris?; Seattle Genetics/Takeda), were presented during the annual meeting of the American Society of Clinical Oncology (ASCO), taking place May 31 to June 4, 2019 in Chicago, Ill.
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical HL and expressed on the surface of several types of peripheral T-cell lymphomas (PTCL),
These novel agents are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
Brentuximab vedotinin includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), using a proprietary technology developped by Seattle Genetics.
The linker system used is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
The ECHELON-1 analysis highlights a three-year update of this phase III clinical trial evaluating brentuximab vedotin in combination with adriamycin, vinblastine and dacarbazine (AVD) compared to adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in stage III or IV frontline classical Hodgkin lymphoma (HL) patients, including analyses by cycle 2 PET (PET2) status and in patients less than 60 years old.
In two poster presentations results were presented of an evaluation of CD30 expression and response to brentuximab vedotin treatment in the ECHELON-2 phase III clinical trial in peripheral T-cell lymphomas (PTCL) and an analysis of five additional trials in T-cell and B-cell non-Hodgkin lymphomas (NHL).
?We continue to evaluate [brentuximab vedotin] as the foundation of care for patients with CD30-expressing lymphomas,? noted Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.
?Importantly, the ECHELON-1 three-year analysis presented at this meeting demonstrate a robust and durable treatment benefit of [brentuximab vedotin] plus AVD versus ABVD across most subgroups and regardless of PET status. In addition, other [brentuximab vedotin] presentations at the ASCO Meeting include new analyses evaluating response by CD30 expression across several non-Hodgkin lymphoma studies.?
?Tumor expression of CD30 by IHC in B-cell and T-cell non-Hodgkin lymphomas can be quite variable between different patients with the same diagnosis and even between different biopsies within the same patient,? said Steven Horwitz, MD., Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, and a clinical trial investigator of brentuximab vedotin.
?In two poster presentations at this year?s ASCO Annual Meeting, results of the analyses suggest that a lower limit or threshold of CD30 expression required for efficacy has not been identified and individual patients may experience clinical benefit from brentuximab vedotin regardless of the level of CD30 expression.?
3-year Update of the ECHELON-1 Study
The first poster presentation (Abstract #7532) examined progression-free survival (PFS) outcomes per investigator assessment in the intent-to-treat population of 1,334 patients at three-years by PET status and in patients less than 60 years old.
As previously reported, the ECHELON-1 trial achieved its primary endpoint with the combination of brentuximab vedotin plus AVD resulting in a statistically significant improvement in modified PFS versus the control arm of ABVD as assessed by independent review facility (IRF; hazard ratio [HR] 0.77; p-value=0.035).
Modified PFS was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy per IRF followed by subsequent anticancer therapy.
Key findings from these analyses include:
- The three-year PFS for all patients in the brentuximab vedotin plus AVD arm was 83.1% compared to 76% in the ABVD arm (HR 0.70), a difference of 7.1%.
- PFS benefit at three-years for brentuximab vedotin plus AVD was observed for all patients independent of PET2 status, including in patients who are less than 60 years old.
- PET2-negative result was 85.8 percent in the brentuximab vedotin plus AVD arm compared to 79.5% in the ABVD arm (HR 0.69), a difference of 6.3%.
- PET2-positive result was 67.7% in the brentuximab vedotin plus AVD arm compared to 51.5% in the ABVD arm (HR 0.59), a difference of 16.2%.
- Consistent improvement in PFS was observed among patients treated with brentuximab vedotin plus AVD compared with ABVD across the majority of pre-specified subgroups, including disease stage, age and prognostic score.
- As previously reported at the primary analysis, on the brentuximab vedotin plus AVD arm, peripheral neuropathy events were observed in 67% of patients compared to 43% in the ABVD arm.
The three-year analysis shows that among patients with peripheral neuropathy, 78% of in the brentuximab vedotin plus AVD arm and 83 percent in the ABVD arm reported complete resolution or improvement at last follow-up.
Statistically significant improvement
As reporsted in December 2018 by Horwitz et al in The Lancet, the phase III ECHELON-2 trial met its primary endpoint with the combination of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (CHP) resulting in a statistically significant improvement in PFS versus the control arm of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) per Blinded Independent Central Review (HR=0.71; p-value=0.0110).
In addition, overall survival in the brentuximab vedotin plus CHP arm was statistically significant compared to CHOP (HR=0.66; p-value=0.0244).These results were included in a poster presentation (Abstract #7538).
Complete remission (CR) rate (p-value=0.0066) and objective response rate (ORR; p-value=0.0032) for the brentuximab vedotin plus CHP arm were also significantly increased. CD30 expression is a hallmark of systemic anaplastic large cell lymphoma (sALCL), but it is variably expressed among non-sALCL PTCL subtypes.
As a lack of correlation between CD30 expression and response to brentuximab vedotin has been previously reported, an analysis was conducted to examine response to brentuximab vedotin plus CHP by CD30 expression in 57 patients with angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) in the ECHELON-2 study, the two histologies with variable expression.
Key findings of this exploratory analysis include:
- Among AITL and PTCL-NOS patients, the ORR in patients treated with brentuximab vedotin plus CHP was independent of the level of CD30 expression. CRs and PRs were observed in patients with all levels of CD30 expression, including those with the lowest level of 10%.
- The duration of complete response was not associated with CD30 expression level for patients with AITL or PTCL-NOS.
Five Trials in PTCL, CTCL, and B-cell Lymphomas
Exploratory analyses of the response to brentuximab vedotin by CD30 Expression (Abstract #7543, poster presentation) were conducted to examine the correlation between pretreatment CD30 expression level and ORR for patients with CD30 expression greater than or equal to 10%, less than 10%, or undetectable (0%) by immunohistochemistry (IHC).
This analysis examined CD30 expression levels of 275 patients across five clinical studies in relapsed or refractory PTCL, cutaneous T-cell lymphoma (CTCL), and B-cell NHL. All patients in this analysis were treated with brentuximab vedotin monotherapy. The key findings include:
- Responses were observed with brentuximab vedotin treatment in patients with all levels of CD30 expression, including in patients with no detectable CD30 expression by IHC.
- Response to brentuximab vedotin was not associated with CD30 expression level.
 Straus DJ, D?ugosz-Danecka M, Alekseev S, Ill?s ?, Picardi M, Lech-Maranda E, Feldman T, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma: Three-year update of the ECHELON-1 study. J Clin Oncol 37, 2019 (suppl; abstr 7532) [Abstract]
 Advani RH, Horwitz SM, Iyer SP, Bartlett NL, Kim WS, Tilly H, Belada D, et al. Response to A+CHP by CD30 expression in the ECHELON-2 trial. J Clin Oncol 37, 2019 (suppl; abstr 7538) [Abstract]
 Jagadeesh D, Horwitz SM, Bartlett NL, Advani RH, Jacobsen ED, Duvic M, Gautam A, et al, Response to brentuximab vedotin by CD30 expression: Results from five trials in PTCL, CTCL, and B-cell lymphomas. J Clin Oncol 37, 2019 (suppl; abstr 7543) [Abstract]