On December 7, 2018 Seattle Genetics, Inc. (Nasdaq: SGEN) and Takeda Pharmaceutical Company Limited (TSE: 4502) reported that ECHELON- step 3 were presented in an oral session 60 in theAnnual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Seattle Genetics, DEC 7, 2018, View Source [SID1234531953]). The data demonstrated that first-line treatment with ADCETRIS (brentuximab vedotin) in combination with CHP (cyclophosphamide, doxorubicin, prednisone) is effective in prolonging progression-free survival (PFS) and overall survival (OS) with a profile comparable to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), a current standard of treatment in patients with CD30-expressing T-cell peripheral lymphomas (LPCT). These data were also published online in The Lancet. ADCETRIS is an antibody-drug (ADC) conjugate directed to CD30, which is expressed on the surface of various types of LPCT.
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Positive results from the top line of the Phase 3 ECHELON-2 clinical trial were previously reported in October 2018. In November 2018, ADCETRIS was approved by the Food and Drug Administration of the United States (FDA) for adults with systemic anaplastic lymphoma large cells (sALCL) or other LPCT expressing CD30, including angioimmunoblastic T-cell lymphoma and LPCT not specified in combination with CHP. ECHELON-2 data were the basis of a Supplemental Biological Permit (SLB), which was reviewed by the FDA under its Real-Time Oncology Review Pilot Program and approved less than two weeks after the complete submission of supplemental SLB.
"As physicians, we are always on the lookout for new strategies to address unmet needs in aggressive blood cancers and ADCETRIS has proven to be one of those agents with benefit to patients in various types of lymphoma and now in first-line LPCT," said Steven. Horwitz, MD, Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center in New York. "This research is important for patients because physicians now have a novel approach to treating newly diagnosed patients with LPCT expressing CD30, a group of aggressive cancers.Data from ECHELON-2 demonstrate that ADCETRIS plus CHP are superior in prolonging progression-free survival and overall survival compared to a current standard of treatment, CHOP, a multi-agent chemotherapy regimen that we have been using in practice for several decades. "
"This is the sixth FDA-approved indication for ADCETRIS in malignant lymphoid tumors and the second as a first-line treatment in combination with chemotherapy," said Roger Dansey, MD, medical director of Seattle Genetics. "Data presented today at ASH (Free ASH Whitepaper) note that the combination of ADCETRIS provides clinically significant benefits for patients with previously untreated LPCT and has the potential to be practice shifting for such patients. "
"We are pleased to share these impressive results from the ECHELON-2 study, which is based on the efficacy and safety observed with ADCETRIS in various CD30-positive lymphomas," said Jesús Gómez-Navarro, MD, vice president and research director and Takeda Clinical Development in Oncology. "The study demonstrated clinically significant results and was the first randomized first-line LPCT Phase 3 trial to show improvement in overall survival. Establishing an optimal therapy for LPCT has been a challenge for clinicians and these findings represent progress in meeting the unmet needs of people living with this serious illness.We look forward to working with regulatory authorities in our territory to bring a possible new treatment option to patients with LPCT. "
The ECHELON-2 trial: Results of a randomized, double-blind, active-controlled phase III study of brentuximab vedotin and CHP (A + CHP) versus CHOP in first-line treatment of patients with peripheral CD30 + T cell lymphomas ( abstract # 997, oral presentation on December 3, 2018 at 6:15 pm at the San Diego Convention Center, Room 6F)
ECHELON-2 is a multicenter, double-blind, randomized, global study evaluating ADCETRIS as part of a first-line chemotherapy regimen in patients with previously untreated LPCT who express CD30. The primary endpoint is SLP by Independent Central Blind Review (BICR), with events defined as progression, death, or chemotherapy for residual or progressive disease. Major secondary endpoints include SLP in patients with sALCL, complete remission rate (RC), SG, and objective response rate (ORT). ECHELON-2 recruited 452 patients (226 in each segment) at 132 sites in 17 countries in North America, Europe, Asia-Pacific and the Middle East. The mean age of the patients was 58 years.
The main conclusions, which will be presented by Dr. Steven Horwitz and published in The Lancet , include:
The ECHELON-2 study reached its primary endpoint with ADCETRIS plus CHP demonstrating a statistically significant improvement in PFS, as assessed by a BICR (hazard ratio [IR] = 0.71, p = 0.0110). This corresponds to a 29% reduction in the risk of progression, death or need for additional antineoplastic therapy for residual or progressive disease.
After an average follow-up time of 36.2 months, the median PFS in ADCETRIS plus CHP control was 48.2 months (95% CI, 35.2% non-assessable) compared to 20.8 months (95% CI, , 12.7-47.6) in the control segment according to the BICR evaluation. The three-year SLP was 57.1% for ADCETRIS plus CHP compared to 44.4% in the control segment.
According to the investigator’s evaluation, ADCETRIS plus CHP demonstrated a statistically significant improvement in PFS (RI = 0.70, p value = 0.0096).
SG in the ADCETRIS plus CHP segment was statistically significant compared to CHOP (RI = 0.66, p = 0.0244). This corresponds to a 34% reduction in the risk of death.
After an average follow-up of 42.1 months, the median OS was not reached for any of the study segments. The SG estimated at three years was 76.8% for ADCETRIS plus CHP, compared to 69.1% for CHOP.
All other important secondary endpoints, including rate of CR and TRO, in addition to SLP in patients with sALCL, were statistically significant in favor of the ADCETRIS plus CHP segment. According to the BICR, the CR rate (68% versus 56%, respectively) and ORT (83% versus 72%, respectively) for the ADCETRIS plus CHP segment were significantly higher than those treated with CHOP (p = 0 value , Î »max and value of p = 0.0032, respectively). According to the investigator’s evaluation, the rate of CR and ORT showed a similar benefit for the ADCETRIS segment plus CHP versus CHOP (p value = 0.0043 and p value = 0.0018, respectively).
Excluding consolidated stem cell transplantation or radiotherapy to consolidate response to initial therapy, 74% of patients in the ADCETRIS plus CHP segment versus 58% of CHOP patients did not require subsequent anti-neoplastic therapies for residual or progressive disease. Of the 226 patients who received CHOP, 49 (22%) received subsequent treatment with a therapy containing ADCETRIS.
The safety profile of ADCETRIS plus CHP in the ECHELON-2 trial was comparable to that of CHOP and consistent with the established safety profile of ADCETRIS in combination with chemotherapy.
Os eventos adversos relacionados com o tratamento mais comuns de qualquer grau que ocorreram em 20% ou mais dos pacientes no segmento ADCETRIS mais CHP e CHOP foram: náusea (46 e 38%, respectivamente), neuropatia sensitiva periférica (45 e 41%, respectivamente), neutropenia (38% cada), diarreia (38 e 20%, respectivamente), obstipação (29 e 30%, respectivamente), alopecia (26 e 25%, respectivamente), pirexia (26 e 19%, respectivamente), vômitos (26 e 17%, respectivamente), fadiga (24 e 20%, respectivamente) e anemia (21 e 16%, respectivamente).
The most common adverse events of Grade 3 or higher that occurred in the ADCETRIS plus CHP and CHOP segments were: neutropenia (35 and 34%, respectively) and anemia (13 and 10%, respectively).
The incidence and severity of neutropenia were similar between study segments and lower in the subgroup of patients receiving primary prophylaxis with granulocyte colony stimulating factor. Febrile neutropenia was reported in 41 patients (18%) in the ADCETRIS plus CHP segment and 33 patients (15%) in the CHOP segment.
Treatment of patients with peripheral neuropathy was observed in 117 patients (52%) in the ADCETRIS plus CHP segment and 124 patients (55%) in the CHOP segment, with a majority of patients with a maximum severity of Grade 1 (64% and 71%, respectively). In the latter follow-up, peripheral neuropathy returned to the baseline or decreased by 50% in ADCETRIS plus CHP patients versus 64% in the CHOP segment, and the mean resolution time was 17 weeks and 11.4 weeks, respectively.
Adverse events leading to death occurred in seven patients (3%) in the ADCETRIS plus CHP segment and nine patients (4%) in the CHOP segment.
See the Important Safety Information, including the Warning in the box, at the end of this press release.
About T-cell lymphomas
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two main categories of lymphoma: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. There are over 60 non-Hodgkin lymphoma subtypes that are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B lymphocytes; and T-cell lymphomas, which develop from abnormal T lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T cell lymphomas can be aggressive (fast growing) or indolent (slow growing).
About ADCETRIS (brentuximab vedotin)
ADCETRIS is being tested in more than 70 ongoing clinical trials for CD30-expressing lymphomas. These include the completed Phase 3 ECHELON-2 assay on first-line peripheral T-cell lymphomas (also known as mature T-cell lymphoma), the completed Phase 3 ECHELON-1 assay on untreated Hodgkin’s lymphoma and the ALCANZA assay stage of T-cell lymphoma.
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody linked by a protease cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), using proprietary technology from Seattle Genetics. The ADC employs a binding system that is designed to be stable in the bloodstream, but to release MMAE after internalization into CD30-expressing tumor cells.
Injection of ADCETRIS for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other peripheral CD30-expressing T-cell lymphomas (LPCT), including angioimmunoblastic T cells and unspecified LPCT, in combination with cyclophosphamide, doxorubicin and prednisone, (2) non-previously treated classic III or IV Hodgkin’s lymphoma (LHc) (III) in combination with doxorubicin, vinblastine and dacarbazine; (3) LHc with high risk of relapse or progression such as post-autologous stem cell transplantation (ASCT) consolidation,
Health Canada granted approval of ADCETRIS with conditions for relapsed or refractory Hodgkin’s lymphoma and sALCL in 2013, and unconditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of patients with Hodgkin’s lymphoma at risk increased relapse or progression.
ADCETRIS received a conditional marketing authorization from the European Commission in October 2012. The indications approved in Europe are: (1) for the treatment of adult patients with relapsed or refractory Hodgkin’s lymphoma after ASCT or after at least two therapies when treating ASCT or multi-agent chemotherapy is not a treatment option, (2) treatment of adult patients with recurrent or refractory slam, (3) for the treatment of adult patients with CD30 positive Hodgkin’s lymphoma at increased risk of relapse or progression after ASCT, and (4) for the treatment of adult patients with cutaneous CD30-positive T-cell lymphoma (CTCL) after at least one prior systemic therapy.
ADCETRIS has received marketing authorization from regulatory authorities in 72 countries for relapsed or refractory Hodgkin’s lymphoma and sALCL. Please refer to the important safety information, including the Warning in the box, below.
Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has marketing rights in the US and Canada, and Takeda has the right to market ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a half-way basis, except in Japan, where Takeda is solely responsible for development costs.