Adcetris Combo Continues to Show Better Results Than Chemotherapy Alone, Phase 3 Update Reveals

Seattle Genetics‘ Adcetris (brentuximab vedotin) in combination with standard chemotherapy continues to show better clinical activity than bleomycin plus standard chemotherapy, as a front-line treatment for patients with Hodgkin’s lymphoma, updated Phase 3 data shows.

Three-year data from the company’s randomized, open-label ECHELON-1 Phase 3 trial (NCT01712490) was recently announced in a poster presentation, “Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma: Three-year update of the ECHELON-1 study,” at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

Adcetris is an antibody-drug conjugate that works by binding to CD30, a protein found at the surface of malignant cancer cells. Once bound, it releases a toxic compound called monomethyl auristatin E that kills cancer cells.

ECHELON-1 was designed to compare the effects of standard chemotherapy — Adriamycin (doxyrubicin), vinblastine, and dacarbazine, along with bleomycin (ABVD) — versus Adcetris in combination with standard chemotherapy without bleomycin (AVD) in patients with advanced classical Hodgkin’s lymphoma.

The trial had previously met its primary objective, showing that patients on Adcetris combined with standard chemotherapy had significantly longer modified progression-free survival (PFS) than those receiving the ABVD regimen. Modified PFS refers to the time patients lived without their disease worsening and without requiring additional cancer treatments.

Updated data presented at the meeting included 1,334 patients who completed up to six cycles of therapy and whose cancer status was examined by positron emission tomography (PET) three years after starting treatment. The main findings revealed that:

• After three years of follow-up, the PFS rate remained higher among those treated with Adcetris plus AVD than in those treated with ABVD (83.1% versus 76%).
• Three-year PFS benefits associated with Adcetris plus AVD were observed for all patients independent of their PET status, including those younger than 60, regardless of the number of therapy sessions completed.
• As previously reported, patients receiving Adcetris plus AVD had a higher incidence of neuropathy events than did those on the ABVD regimen (67% versus 43%).

“We continue to evaluate Adcetris as the foundation of care for patients with CD30-expressing lymphomas,” Roger Dansey, MD, chief medical officer at Seattle Genetics, said in a press release.

“Importantly, the ECHELON-1 three-year analysis presented at this meeting demonstrate a robust and durable treatment benefit of Adcetris plus AVD versus ABVD across most subgroups and regardless of PET status. In addition, other Adcetris presentations at the ASCO Meeting include new analyses evaluating response by CD30 expression across several non-Hodgkin lymphoma studies,” Dansey added.

In another poster presentation, “Response to A CHP by CD30 expression in the ECHELON-2 trial,” Seattle Genetics discussed the effect of Adcetris on the levels of CD30 in patients with peripheral T-cell lymphomas (PTCL) participating in the Phase 3 ECHELON-2 trial (NCT01777152).

ECHELON-2 was designed to compare the effects of Adcetris in combination with CHP chemotherapy — cyclophosphamide, doxorubicin, and prednisone — versus standard CHOP chemotherapy — cyclophosphamide, doxorubicin, vincristine, and prednisone — alone.

Previous data from ECHELON-2 showed that patients treated with Adcetris plus CHP had a significant improvement in PFS over those treated with standard CHOP chemotherapy. In addition, patients receiving Adcetris plus CHP survived longer and achieved higher rates of complete remission (CR; complete tumor eradication) and objective response rates (ORR; tumor reduction to a predefined amount) than those on CHOP chemotherapy.

At the meeting, investigators presented the findings of an exploratory analysis of ECHELON-2 aimed at determining if patients’ response to Adcetris plus CHP could be affected by the levels of CD30 in a group of 57 patients with angioimmunoblastic T-cell lymphoma (AITL) or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). Key findings revealed that:

• In all patients, the ORR and the duration of CRs were not affected by the levels of CD30.
• CRs and partial responses (PRs, partial tumor eradication) were found among patients with all levels of CD30, including those with the lowest level of 10%.

In the last poster titled, “Response to Brentuximab Vedotin by CD30 Expression: Results from Five Trials in PTCL, CTCL, and B-cell Lymphomas,” the effect of CD30 expression levels on Adcetris treatment response was described in patients with T- and B-cell non-Hodgkin’s lymphoma.

The exploratory analysis included 275 patients participating in five different Phase 2 and 3 trials (NCT01421667; NCT02588651; NCT01578499; NCT01352520; and NCT01396070) who had been diagnosed with relapsed or refractory PTCL, cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin’s lymphoma and were treated with Adcetris alone.

According to findings from the trials, all patients responded to treatment, regardless of the expression levels of CD30, including those with undetectable CD30. These findings were in agreement with data from the exploratory analysis of ECHELON-2.

“Tumor expression of CD30 by IHC [immunohistochemistry] 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, an Adcetris clinical trial investigator from the Memorial Sloan Kettering Cancer Center in New York.

“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,” he added.

In March 2018, the U.S. Food and Drug Administration approved the combination of Adcetris and AVD for the treatment of adults with previously untreated advanced (stage 3 or 4) classical Hodgkin’s lymphoma, based on data from ECHELON-1.

Later, in November 2018, the regulatory agency approved the combination of Adcetris and CHP for the treatment of adults with previously untreated systemic anaplastic large cell lymphoma or other types of peripheral T-cell lymphomas with high expression of CD30, such as AITL or PTCL-NOS, based on findings from ECHELON-2.