Seattle Genetics Announces Additional Analyses of ECHELON-1 and ECHELON-2 Phase 3 Clinical Trials of ADCETRIS® (Brentuximab Vedotin) at the 2019 ASCO Annual Meeting

BOTHELL, Wash.--(BUSINESS WIRE)-- Seattle Genetics, Inc. (Nasdaq:SGEN) today announced additional analyses of results from ECHELON-1 and ECHELON-2, the frontline phase 3 trials of ADCETRIS^® (brentuximab vedotin), at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting taking place May 31 to June 4, 2019 in Chicago. The ECHELON-1 analysis highlights a three-year update of this phase 3 clinical trial evaluating ADCETRIS in combination with AVD (Adriamycin, vinblastine and dacarbazine) compared to ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) 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 addition, two poster presentations evaluate CD30 expression and response to ADCETRIS treatment in the ECHELON-2 phase 3 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). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL and expressed on the surface of several types of PTCL.

“We continue to evaluate ADCETRIS as the foundation of care for patients with CD30-expressing lymphomas,” said 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 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.”

“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, M.D., Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, and an ADCETRIS clinical trial investigator. “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.”

Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical Hodgkin Lymphoma: 3-year Update of the ECHELON-1 Study (Abstract #7532, poster presentation on Monday, June 3, 2019)

This poster presentation examines 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 ADCETRIS 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 ADCETRIS plus AVD arm was 83.1 percent compared to 76 percent in the ABVD arm (HR 0.70), a difference of 7.1 percent.
• PFS benefit at three-years for ADCETRIS 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 ADCETRIS plus AVD arm compared to 79.5 percent in the ABVD arm (HR 0.69), a difference of 6.3 percent.
  • PET2-positive result was 67.7 percent in the ADCETRIS plus AVD arm compared to 51.5 percent in the ABVD arm (HR 0.59), a difference of 16.2 percent.
• Consistent improvement in PFS was observed among patients treated with ADCETRIS 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 ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 67 percent of patients compared to 43 percent in the ABVD arm. The three-year analysis shows that among patients with peripheral neuropathy, 78 percent of in the ADCETRIS plus AVD arm and 83 percent in the ABVD arm reported complete resolution or improvement at last follow-up.

Response to A+CHP by CD30 Expression in the ECHELON-2 Trial (Abstract #7538, poster presentation on Monday, June 3, 2019)

As previously reported, the ECHELON-2 trial met its primary endpoint with the combination of ADCETRIS plus 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 ADCETRIS plus CHP arm was statistically significant compared to CHOP (HR=0.66; p-value=0.0244). Complete remission (CR) rate (p-value=0.0066) and objective response rate (ORR; p-value=0.0032) for the ADCETRIS 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 ADCETRIS has been previously reported, an analysis was conducted to examine response to ADCETRIS 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 ADCETRIS 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 percent.
• The duration of complete response was not associated with CD30 expression level for patients with AITL or PTCL-NOS.

Response to Brentuximab Vedotin by CD30 Expression: Results from Five Trials in PTCL, CTCL, and B-cell Lymphomas (Abstract #7543, poster presentation on Monday, June 3, 2019)

Exploratory analyses were conducted to examine the correlation between pretreatment CD30 expression level and ORR for patients with CD30 expression greater than or equal to 10 percent, less than 10 percent, or undetectable (0 percent) 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 ADCETRIS monotherapy. The key findings include:

• Responses were observed with ADCETRIS treatment in patients with all levels of CD30 expression, including in patients with no detectable CD30 expression by IHC.
• Response to ADCETRIS was not associated with CD30 expression level.

The U.S. Food and Drug Administration (FDA) approved ADCETRIS in combination with AVD for the treatment of adult patients with previously untreated stage III or IV classical HL in March 2018, based on the results of the ECHELON-1 phase 3 clinical trial. The FDA approved ADCETRIS in combination with CHP (cyclophosphamide, doxorubicin, and prednisone) for the treatment of adult patients with previously untreated sALCL or other CD30-expressing PTCL, including AITL and PTCL-NOS based on the results of the ECHELON-2 phase 3 trial, in November 2018.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include three completed phase 3 trials: ECHELON-2 trial in frontline peripheral T-cell lymphomas, ECHELON-1 in previously untreated Hodgkin lymphoma, and ALCANZA in cutaneous T-cell lymphoma. The CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma is ongoing.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection 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 CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression in 2017, adults with pcALCL or CD30-expressing MF who have had prior systemic therapy in 2018, and for previously untreated Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine in 2019.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) for the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy and (5) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with AVD (Adriamycin^®, vinblastine and dacarbazine).

ADCETRIS has received marketing authorization by regulatory authorities in 72 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About Seattle Genetics

Seattle Genetics, Inc. is an emerging multi-product, global biotechnology company that develops and commercializes transformative therapies targeting cancer to make a meaningful difference in people’s lives. ADCETRIS^® (brentuximab vedotin) utilizes the company’s industry-leading antibody-drug conjugate (ADC) technology and is currently approved for the treatment of multiple CD30-expressing lymphomas. Beyond ADCETRIS, the company has established a pipeline of novel targeted therapies at various stages of clinical testing, including three in ongoing pivotal trials for solid tumors. Enfortumab vedotin for metastatic urothelial cancer and tisotumab vedotin for metastatic cervical cancer utilize our proprietary ADC technology. Tucatinib, a small molecule tyrosine kinase inhibitor, is in a pivotal trial for HER2-positive metastatic breast cancer. In addition, we are leveraging our expertise in empowered antibodies to build a portfolio of proprietary immuno-oncology agents in clinical trials targeting hematologic malignancies and solid tumors. The company is headquartered in Bothell, Washington, and has a European office in Switzerland. For more information on our robust pipeline, visit www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

• Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
• Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
• Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Start primary prophylaxis with G-CSF beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III or IV classical HL or previously untreated PTCL. Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses.
• Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
• Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
• Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
• Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
• Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
• PML: Fatal cases of JC virus infection resulting in PML and death have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. Other possible contributory factors other than ADCETRIS include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
• Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
• Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
• Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
• Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Most Common (≥20% in any study) Adverse Reactions: Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia and mucositis

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

For additional Important Safety Information, including BOXED WARNING, please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or http://www.adcetris.com.

Forward-Looking Statements

Certain of the statements made in this press release are forward looking, such as those, among others, relating to the possible uses and benefits of ADCETRIS as the foundation of care for CD30-expressing lymphomas and in certain clinical settings. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the potential lack of efficacy or risk of adverse events associated with the use of ADCETRIS in certain clinical settings. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2019 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

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